Chapter9 Adult Hypothyroidism

Chapter 9. Adult Hypothyroidism

9.1 HISTORY

9.2 DEFINITION AND EPIDEMIOLOGY OF HYPOTHYROIDISMThe full-blown expression of hypothyroidism is known as myxedema. Adultmyxedema escaped serious attention until Gull described it in 1874 1. That it was astate resembling the familiar endemic cretinism, but coming on in adult life, waswhat chiefly impressed Gull. Ord 2invented the term myxedema in 1873. Thedisorder arising from surgical removal of the thyroid gland (cachexia strumipriva)was described in 1882 by Reverdin 3of Geneva and in 1883 by Kocher of Berne 4.After Gull’s description, myxedma aroused enormous interest, and in 1883 theClinical Society of London appointed a committee to study the disease and report itsfindings 5. The committee’s report, published in 1888, contains a significant portionof what is known today about the clinical and pathologic aspects of myxedema. Itis referred to in the following discussion as the Report on Myxedema. The finalconclusion of the 200-page volume are penetrating. They are as follows:

1. That myxedema is a well-defined disease.

2. That the disease affects women much more frequently than men, and that thesubjects are for the most part of middle age.

3. That clinical and pathological observations, respectively, indicate in a decisiveway that the one condition common to all cases is destructive change of thethyroid gland.

4. That the most common form of destructive change of the thyroid gland con-sists in the substitution of a delicate fibrous tissue for the proper glandularstructure.

5. That the interstitial development of fibrous tissue is also observed very fre-quently in the skin, and, with much less frequency, in the viscera, the appear-ances presented by this tissue being suggestive of an irritative or inflammatoryprocess.

6. That pathological observation, while showing cause for the changes in the skinobserved during life, for the falling off the hair, and the loss of the teeth, forthe increased bulk of body, as due to the excess of subcutaneous fat, affords noexplanation of the affections of speech, movement, sensation, consciousness,and intellect, which form a large part of the symptoms of the disease.

7. That chemical examination of the comparatively few available cases fails toshow the general existence of an excess of mucin in the tissues adequatelycorresponding to the amount recorded in the first observation, but that thisdiscrepancy may be, in part, attributed to the fact that tumefaction of the in-teguments, although generally characteristic of myxedema, varies consider-ably throughout the course of the disease, and often disappears shortly beforedeath.

8. That in experiments made upon animals, particularly on monkeys, symptomsresembling in a very close and remarkable way those of myxedema have fol-lowed complete removal of the thyroid gland, performed under antiseptic pre-cautions, and with, as far as could be ascertained, no injury to the adjacentnerves or to the trachea.

9. That in such experimental cases a large excess of mucin has been found to bepresent in the skin, fibrous tissues, blood, and salivary glands; in particular theparotid gland, normally containing no mucin, has presented that substance in

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quantities corresponding to what would be ordinarily found in the submaxil-lary gland.

10. That following removal of the thyroid gland in man in an important propor-tion of the cases, symptoms exactly corresponding with those of myxedemasubsequently develop.

11. That in a considerable number of cases the operation has not been known tohave been followed by such symptoms, the apparent immunity being in manycases probably due to the presence and subsequent development of accessorythyroid glands, or to accidentally incomplete removal, or to insufficiently longobservation of the patients after operation.

12. That, whereas injury to the trachea, atrophy of the trachea, injury of the re-current laryngeal nerves, injury of the cervical sympathetic, and endemic in-fluences, have been by various observers supposed to be the true cases of ex-perimental or of operative myxedema (cachexia strumipriva), there is, in thefirst place, no evidence to show that, of the numerous and various surgicaloperations performed on the neck and throat, involving various organs andtissues, any, save those in which the thyroid gland has been removed, havebeen followed by the symptoms under consideration; that in many of the op-erations on man, and in most, if not all, of the experimental operations made byProfessor Horsley on monkeys and other animals, this procedure avoided allinjury of surrounding parts, and was perfectly antiseptic; that myxedema hasfollowed removal of the thyroid gland in persons neither living in nor havinglived in localities the seat of endemic cretinism; that, therefore, the positive evi-dence on this point vastly outweighs the negative; and that it appears stronglyproved that myxedema is frequently produced by the removal, as well as bythe pathological destruction, of the thyroid gland.

13. That whereas, according to Clause 2, in myxedema women are much more nu-merously affected than men, in the operative form of myxedema no importantnumerical difference is observed.

14. That a general review of symptoms and pathology leads to the belief that thedisease described under the name of myxedema, as observed in adults, is prac-tically the same disease as that named sporadic cretinism when affecting chil-dren; that myxedema is probably identical with cachexia strumipriva; and thata very close affinity exists between myxedema and endemic cretinism.

15. That while these several conditions appear, in the main, to depend on, or tobe associated with, destruction or loss of the function of the thyroid gland, theultimate cause of such destruction or loss is at present not evident.

Hypothyroidism is traditionally defined as deficient thyroidal production of thyroidhormone. The term primary hypothyroidism indicates decreased thyroidal secretionof thyroid hormone by factors affecting the thyroid gland itself; the fall in serumconcentrations of thyroid hormone causes an increased secretion of TSH resultingin elevated serum TSH concentrations. Decreased thyroidal secretion of thyroid hor-mone can also be caused by insufficient stimulation of the thyroid gland by TSH, dueto factors directly interfering with pituitary TSH release (secondary hypothyroidism)or indirectly by diminishing hypothalamic TRH release (tertiary hypothyroidism); inclinical practice it is not always possible to discriminate between secondary and ter-tiary hypothyroidism, which are consequently often referred to as central hypothy-roidism. In rare cases, symptoms and signs of thyroid hormone deficiency are causedby the inability of tissues to respond to thyroid hormone by mutations in the nuclearthyroid hormone receptor TRß; this condition, known as thyroid hormone resistance(see Ch. 16), is associated with an increased thyroidal secretion of thyroid hormonesand increased thyroid hormone concentrations in serum in an attempt of the bodyto overcome the resistance to thyroid hormone. It thus seems more appropriate todefine hypothyroidism as thyroid hormone deficiency in target tissues, irrespectiveof its cause.

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GRADES OF HYPOTHYROIDISMHypothyroidism is a graded phenomenon, ranging from very mild cases in whichbiochemical abnormalities are present but the individual hardly notices symptomsand signs of thyroid hormone deficiency, to very severe cases in which the dangerexists to slide down into a life-threatening myxedema coma. In the development ofprimary hypothyroidism, the transition from the euthyroid to the hypothyroid stateis first detected by a slightly elevated serum TSH, caused by a minor decrease inthyroidal secretion of T4 which doesn’t give rise to subnormal serum T4 concentra-tions. The reason for maintaining T4 values within the reference range is the exquisitesensitivity of the pituitary thyrotroph for even very small decreases of serum T4, asexemplified by the log-linear relationship between serum TSH and serum FT4 1. Afurther decline in T4 secretion results in serum T4 values below the lower normallimit and even higher TSH values, but serum T3 concentrations remain within the ref-erence range. It is only in the last stage that subnormal serum T3 concentrations arefound, when serum T4 has fallen to really very low values associated with markedlyelevated serum TSH concentrations (Figure 9-1). Hypothyroidism is thus a gradedphenomenon, in which the first stage of subclinical hypothyroidism may progressvia mild hypothyroidism towards overt hypothyroidism (Table 9-1) 3.

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Figure 1. Individual and median values of thyroid function tests in patients withvarious grades of hypothyroidism. Discontinuous horizontal lines represent upperlimit (TSH) and lower limit (FT4,T3) of the normal reference ranges. (Reproducedwith permission) (2)

Table 1. Grades of hypothyroidism

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Grade 1 Subclinicalhypothyroidism

TSH + FT4 N T3 N(+)

Grade 2 Mildhypothyroidism

TSH + FT4 - T3 N

Grade 3 Overthypothyroidism

TSH + FT4 - T3 -

+, above upper normal limit; N, within normal reference range;-, below lower normal limit.

Maintenance of a normal serum T3 concentration until a relatively late stage in the de-velopment of hypothyroidism obviously serves as an appropriate mechanism of thebody to counteract the impact of diminishing production of T4. It is accomplished bya preferential thyroidal secretion of T3: the increased secretion of TSH enhances thesynthesis of T3 more than that of T4 and stimulates thyroidal 5’-monodeiodinationof T4 into T3 4,5. It explains why sometimes a slightly elevated serum T3 is found inthe early stage of development of hypothyroidism. About 80% of the daily produc-tion rate of T3 is generated in extrathyroidal tissues via the conversion of T4 into T3.The peripheral tissues also have a defense mechanism against developing hypothy-roidism by increasing the overall fractional conversion rate of T4 into T3 6.

EPIDEMIOLOGY OF HYPOTHYROIDISMThyroid hormone resistance syndromes are seldom the cause of hypothyroidism; thenumber of registered patients approximates one thousand (see Ch. 16). Central hy-pothyroidism is also rare; its precise prevalence is unknown, but has been estimatedas 0.005% in the general population 7. Primary hypothyroidism, in contrast, is a veryprevalent disease worldwide. It can be endemic in iodine-deficient regions (see Ch.20), but it is also a common disease in iodine-replete areas as evident from preva-lence and incidence figures reported in a number of population-based studies 8-14.The most extensive data has been obtained from the Whickham Survey, a study of2779 adults randomly selected of the general population in Great Britain who wereevaluated between 1972 and 1974 and again twenty years later 8,9. Most striking arethe high prevalence of thyroid microsomal (peroxidase) antibodies and of (subclini-cal) hypothyroidism, and the marked female preponderance (Table 9-2).

Table 2. Prevalence and incidence of thyroid antibodies and hypothyroidism in theWhickham survey (8,9).

Women Men

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Women MenPrevalence

• microsomalantibodies

• thyroglobulinantibodies

• subclinicalhypothyroidism

• hypothyroidism

• 103 per 1000

• 30 per 1000

• 75 per 1000

• 18 per 1000

• 27 per 1000

• 9 per 1000

• 28 per 1000

• 1 per 1000

Incidence hypothyroidism 4.1 per 1000 per yr 0.6 per 1000 per yr

The mean incidence of spontaneous hypothyroidism in women was 3.5/1000 sur-vivors/year, that of hypothyroidism after destructive treatment for thyrotoxicosis0.6/1000 survivors/year; similar figures were obtained in those who had deceasedduring follow-up. The hazard rate (the probability to develop hypothyroidism) in-creased with age; the mean age at diagnosis of hypothyroidism in women was 60years. Studies from other countries like the USA 10,11, Japan 12and Sweden 13reportessentially similar data.

Of particular interest are risk factors for development of hypothyroidism. In womensurvivors of the Whickham Survey, the risk of developing overt hypothyroidism was4.3% per year if both raised serum TSH and thyroid antibodies were present initially,2.6% per year if raised serum TSH was present alone, and 2.1% per year if thyroidantibodies were present alone 9. At the time of follow-up twenty years later, hypothy-roidism had developed in these three groups in 55%, 33% and 27% respectively, butonly in 4% if initial serum TSH was normal and thyroid antibodies were absent. Theprobability of developing hypothyroidism already increases at a rise in serum TSHabove 2 mU/L as shown in Figure 9-2, in thyroid antibody positive as well as inthyroid antibody negative women; it also increases with higher titres of thyroid mi-crosomal antibodies 9,15.

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Figure 2. Logit probability (log odds) for the development of hypothyroidism as afunction of TSH values at first survey during a 20-year follow-up of 912 women inthe Whickham Survey. (Reproduced with permission)(9).

9.3 CAUSES OF HYPOTHYROIDISMA variety of functional or structural disorders may lead to hypothyroidism, the sever-ity of which depends on the degree and duration of thyroid hormone deprivation. Aclassification according to etiology appears in Table 9-3. The two principal categoriesof hypothyroidism are primary, or thyroprivic, caused by an inherent inability of thethyroid gland to supply a sufficient amount of the hormone, and trophoprivic hy-pothyroidism, due to inadequate stimulation of an intrinsically normal thyroid glandresulting from a defect at the level of the pituitary (secondary hypothyroidism) or thehypothalamus (tertiary hypothyroidism). In a third (uncommon) form of hypothy-roidism, regulation and function of thyroid gland are intact. Instead, manifestationsof hormone deprivation arise from a disorder in the target tissues that reduces theirresponsiveness to the hormone (peripheral tissue resistance to thyroid hormone) orthat inactivates the hormone (in massive infantile hemangiomas).

The most common cause of hypothyroidism is destruction of the thyroid gland bydisease or as a consequence of vigorous ablative therapies to control thyrotoxicosis.Primary hypothyroidism may also result from inefficient hormone synthesis causedby inherited biosynthetic defects (see Ch. 16), a deficient supply of iodine (see Ch.20), or inhibition of hormonogenesis by various drugs and chemicals (see Ch. 5). Insuch instances, hypothyroidism is typically associated with thyroid gland enlarge-ment (goitrous hypothyroidism).

Table 3. Causes of hypothyroidism

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1. Central (hypothalamic/pituitary) hypothyroidism

a. Loss of functional tissue

i. tumors (pituitary adenoma, craniopharyngioma,meningioma, dysgerminoma, glioma, metastases)

ii. trauma (surgery, irradiation, head injury)

iii. vascular (ischemic necrosis, hemorrhage, stalkinterrruption, aneurysm of internal carotid artery)

iv. infections (abcess, tuberculosis, syphilis, toxoplasmosis)

v. infiltrative (sarcoidosis, histiocytosis, hemochromatosis)

vi. chronic lymphocytic hypophysitis

vii. congenital (pituitary hypoplasia, septooptic dysplasia,basal encephalocele)

b. Functional defects in TSH biosynthesis and release

i. mutations in genes encoding for TRH receptor, TSHŸ, orPit-1

ii. drugs: dopamine; glucocorticoids; L-thyroxinewithdrawal

2. Primary (thyroidal) hypothyroidism

a. Loss of functional thyroid tissue

i. chronic autoimmune thyroiditis

ii. reversible autoimmune hypothyroidism (silent andpostpartum thyroiditis, cytokine-induced thyroiditis).

iii. surgery and irradiation (131I or external irradiation)

iv. infiltrative and infectious diseases, subacute thyroiditis

v. thyroid dysgenesis

b. Functional defects in thyroid hormone biosynthesis and release

i. congenital defects in thyroid hormone biosynthesis

ii. iodine deficiency and iodine excess

iii. drugs: antithyroid agents, lithium, natural and syntheticgoitrogenic chemicals

3. "Peripheral" (extrathyroidal) hypothyroidism

a. Thyroid hormone resistance

b. Massive infantile hemangioma8


9.3.1. CENTRAL HYPOTHYROIDISMHypothalamic disorders cause reduced TSH secretion by impairing the productionor transport of TRH to the pituitary gland. Hypothyroidism may occur because thepituitary secretes TSH in insufficient quantities, or secretes TSH with an abnormalglycosylation pattern which reduces the biologic activity of TSH 1,2,3. Treatment withoral TRH restores the biologic activity of TSH, suggesting that deficient hypotha-lamic TRH release induces both quantitative and qualitative abnormalities of TSHsecretion. TSH molecules with reduced biologic activity may retain their immuno-logic reactivity in TSH immunoassays, explaining the sometimes observed slightlyincreased values of serum TSH (up to 10 mU/l) in central hypothyroidism 18 , 23.

The term central hypothyroidism is preferred because it is not always possible todistinguish between hypothalamic and pituitary causes. Central hypothyroidism isalso associated with a decreased nocturnal TSH surge (due to loss of the nocturnalincrease in TSH pulse amplitude under preservation of the nighttime increase in TSHpulse frequency), which further hampers maintenance of a normal thyroid function4,5.

Central hypothyroidism is a relatively rare condition occurring about equally in bothsexes. Congenital cases of central hypothyroidism are due to structural lesions likepituitary hypoplasia, midline defects and Rathke’s pouch cysts, or to functional de-fects in TSH biosynthesis and release like loss-of-function’ mutations in genes en-coding for the TRH receptor 6, the TSH-beta subunit 7,8, and the pituitary-specifictranscription factor Pit-1 9. Familial hypothyroidism due to TSH$ gene mutationsfollows an autosomal mode of inheritance. The $-subunit (118 aa) heterodimerizesnoncovalently with the "-subunit through a segment called ?seat-belt? (aa 88-105).The described mutations of the TSH$ gene hamper dimerization with the "-subunitand thereby the correct secretion of the mature TSH heterodimer: Q42X and Q29Xintroduce a premature stop codon resulting in a truncated TSH$ subunit, G29R is anonsense mutation preventing dimer formation, and C105)114X is a frameshift mu-tation causing disruption of one of the two disulfide bridges stabilizing the seat beltregion 7,8,19,20. Plasma TSH levels are variable, the TSH response to TRH is impairedbut PRL secretion is normal, and plasma glycoprotein hormone "-subunits are high 19.The target genes of Pit-1 include those of GH, PRL, and TSH . The few patients withidentified Pit-1 deficiency had both GH and PRL deficiency; the occurrence of hy-pothyroidism due to TSH insufficiency is variable 9. Cases of central hypothyroidismin childhood are mostly caused by craniopharyngioma (TSH deficiency in 53%) orcranial irradiation for brain tumors like dysgerminoma (TSH deficiency in 6%) orhematological malignancies 24 . Prophylactic cranial irradiation of the central ner-vous system in children with acute lymphoblastic leukaemia did not have an adverseeffect on thyroid function within a median follow-up time of 8 years 21.

Central hypothyroidism in adults is most frequently due to pituitary macroadeno-mas and pituitary surgery or irradiation 22. The occurrence of TSH deficiency oc-curs usually after loss of GH and gonadotropin secretion. Return to euthyroidism issometimes observed after selective adenomectomy 10. Radiotherapy of brain tumorsor pituitary adenomas is followed by hypothyroidism in up to 65%; the onset of hy-pothyroidism may be seen many years after radiotherapy 11,12. Less common causes ofadult central hypothyroidism are head injury 13, 25, ischemic necrosis due to postpar-tum hemorrhage (Sheehan’s syndrome), pituitary apoplexy, infiltrative diseases, andlymphocytic hypophysitis 14. Lymphocytic hypophysitis seems to be an autoimmunedisease; it occurs predominantly in women, especially during and after pregnancy,and the clinical picture is characterized by a pituitary mass and hypopituitarism 26 .

Dopamine infusion inhibits the release of TSH, which may decrease T4 productionrate by 56% 15. Supraphysiological amounts of endogenous or exogenous glucocor-ticoids also dampen the release of TSH, but give seldom rise to decreased serum T4values. The same is true for treatment with long-acting somatostatin analogs. A tran-

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sient decrease of TSH secretion can be observed after withdrawal of TSH-suppressivedoses of L-thyroxine, which may last up to 6 weeks 16.

A new and novel cause of iatrogenic central hypothyroidism is from the administra-tion of the RXRg-selective ligand, bexarotene (Targretin). This medication is highlyeffective in cutaneous T cell lymphoma, but as reported by Sherman et al, up to 70%of patients treated with daily doses > 300 mg/m 2had symptoms and signs of hy-pothyroidism. This was associated with reduction of serum TSH to an average of0.05 mU/l, and reduction of free T4 from 12.9 pmol/l to 5.8 pmol/l 17 . In vitro stud-ies have shown that activity of the TSHb subunit gene promoter is suppressed by9-cis-retinoic acid and bexarotene 17 , but other studies have not confirmed this 27 .The condition can be appropriately treated by administration of thyroid hormone. (17)

9.3.2 CHRONIC AUTOIMMUNE THYROIDITISChronic autoimmune thyroiditis may eventually cause hypothyroidism, mainly viadestruction of thyrocytes (see also Ch. 7). In goitrous autoimmune hypothyroidism(the classical variant originally described by Hashimoto) the histology of the thy-roid gland is characterized by massive lymphocytic infiltration with formation ofgerminal centers and oxyphilic changes of thyrocytes. In atrophic myxedema fibrosisis predominant, next to lymphocytic infiltration. The diffise Hashimoto goiter has apeculiar firm consistency like rubber; the goiter may regress with time but can per-sist in many cases 1. In some instances the patient presents with an initial transienthyperthyroid stage, called Hashitoxicosis’. The term Hashimoto’s disease is gener-ally used to indicate auto-immune destruction of thyrocytes which may eventuallyresult in hypothyroidism although many cases remain euthyroid (see also Ch. 8).The serological hallmark of Hashimoto’s disease is the presence of high titers of thy-roid peroxidase (TPO) autoantibodies, formerly known as thyroid microsomal anti-bodies. The opposite of Hashimoto’s disease is Graves’ disease characterized by thepresence of TSH receptor stimulating antibodies resulting in hyperthyroidism. Thetwo disease entities frequently overlap, and can be viewed as the opposite ends ofa continuous spectrum of autoimmune thyroid disease. Indeed, many patients withGraves’ disease have TPO antibodies, and some case reports mention classical fea-tures of Graves’ disease like exophthalmos and pretibial myxedema in the presenceof hypothyroidism without any previous thyrotoxicosis 2. TSH receptor blocking an-tibodies do occur in Hashimoto’s disease, contributing to thyroid atrophy and hy-pothyroidism; they are more prevalent in Japanese than in Caucasian patients 3,4.TSH receptor antibodies in Hashimoto’s disease are negatively correlated to serumFT4 and thyroid size 5.

The clinical manifestation of Hashimoto’s disease with respect to thyroid functionand thyroid size depends on the net effect of the various immunologic effector mech-anisms involved in chronic autoimmune thyroiditis. Genetic and environmental fac-tors may modulate the expression of the disease. Autoimmune hypothyroidism inCaucasians is weakly associated with HLA-DR3; its prevalence is higher in regionswith a high ambient iodine intake than in iodine-deficient areas 6,7.

9.3.3 REVERSIBLE AUTOIMMUNE HYPOTHYROIDISMChronic autoimmune thyroiditis. Conventional wisdom has it that once hypothy-roid’ means always hypothyroid’. Indeed, the vast majority of patients with hypothy-roidism due to chronic autoimmune thyroiditis require life-long thyroxine replace-ment therapy, but spontaneous recovery does occur in about 5% 1. Return to the eu-thyroid state is apparently more frequent in countries like Japan, where - at a highambient iodine intake - restriction of dietary iodine alone may induce a remission2 ,35 .

Conditions that increase the likelihood of spontaneous recovery are the presence ofa goiter, a relatively high thyroidal radioiodine uptake, and a preserved increase of

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T3 after the administration of TRH during thyroxine treatment 2,3,4. The spontaneousevolution from hypothyroidism back to euthyroidism has been related to the disap-pearance of TSH receptor blocking antibodies 5. Changes in the titers of co-existingTSH receptor blocking and stimulating antibodies explain the sometimes observedalternating course of hypothyroidism and hyperthyroidism in the same subject 6.

Silent thyroiditis and postpartum thyroiditis. Silent or painless thyroiditis and post-partum thyroiditis are variant forms of chronic autoimmune thyroiditis. The autoim-mune reaction causes a mainly T-cell mediated destructive thyroiditis, which how-ever is self-limiting. The characteristic course of the disease is thus first a thyrotoxicstage due to the release of stored hormone from the disrupted follicles, followed bya hypothyroid stage during the recovery towards a normal thyroid architecture; usu-ally euthyroidism is restored within a few months (see also Ch. 8). In many cases thedisease remains unnoticed, as clinical symptoms and signs are mostly limited. In thepostpartum period it is also quite natural to attribute emerging complaints - espe-cially if they are nonspecific in nature - to the aftermath of pregnancy and the workload of having a baby. Postpartum thyroiditis is, however, a rather common event,with an incidence of 4-6% as evident from several population-based studies 7,8. Theincidence in type I diabetes mellitus is four times higher, up to 25% 9. Postpartumthyroiditis can be predicted to a certain extent from the presence of TPO antibodiesin the serum of pregnant women in the first trimester: a titer of =100 kU/l at 2 weekshas a positive predictive value of 0.50 and a negative predictive value of 0.98 in thisrespect 8. The titer of TPO antibodies decreases in the second and third trimester, andincreases again in the postpartum period .

Women who have experienced postpartum thyroiditis, have a 40% risk to developagain postpartum thyroiditis after a following pregnancy. About 20-30% of womenwith postpartum thyroiditis will develop permanent hypothyroidism within 5 years;the risk is higher in women with high titers of TPO-antibodies 10. A subset of womenwith postpartum thyroiditis experience only a thyrotoxic phase; they are less at riskfor later development of hypothyroidism 11. Maternal TPO antibodies are associatedwith depression in the postpartum period 12and with impaired child development13. A low maternal FT4 concentration during early pregnancy is also associated withimpaired psychomotor development in infancy 14.

Cytokine-induced thyroiditis. Cytokines are heavily involved in immune reactions(see Ch. 7), and it is thus not surprising that treatment with pharmacological doses ofcytokines may induce autoimmune diseases in susceptible subjects. Treatment withinterleukin-2 or interferon-a of patients with malignant tumors or hepatitis B or Cis causally related to the occurrence of TPO-antibodies and the development of ab-normal thyroid function 15,16,17. The course of cytokine-induced thyroiditis resemblesthat of silent and postpartum thyroiditis: a rather sudden onset, a thyrotoxic stagefollowed by a hypothyroid stage, and usually return to euthyroidism after discontin-uation of cytokine treatment. The incidence is about 5-20%; it occurs more often infemales with pre-existent thyroid antibodies 18 .

9.3.4 POSTOPERATIVE AND POSTRADIATIONHYPOTHYROIDISMSurgery. An important cause of hypothyroidism is surgical removal of the gland.Up to 40 percent of patients who undergo thyroidectomy for Graves’ disease de-velop hypothyroidism (1). Most patients become hypothyroid in the first year aftersurgery; immediate postoperative hypothyroidism may resolve spontaneously by 6months. After the first year the cumulative incidence of hypothyroidism rises by 1-2% per year. The frequency of hypothyroidism depends on the zeal of the surgeonand on other factors, such as the function of the thyroid remnant or the presence ofactive thyroiditis. Its occurrence correlates with the presence of antibodies to thyroidantigens. Thus, progressive destruction of residual tissue by thyroiditis may be thepathogenic mechanism. Hypothyroidism after surgical removal of multinodular goi-

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ter is less common (about 15%). Myxedema occurs almost invariably after subtotalthyroidectomy for Hashimoto’s thyroiditis and after removal of lingual thyroids.

Radioiodine. A leading cause of hypothyroidism is radioactive iodine (RAI) treat-ment of Graves’ disease. The frequency with which hypothyroidism supervenes RAItherapy is dependent on multiple factors, the principal one being the dose of RAIadministered. The incidence of hypothyroidism 10 years after treatment is reportedas high as 70 percent 1. Hypothyroidism frequently develops already in the first yearafter treatment (with spontaneous return to euthyroidism in some patients), but itmay not be manifest until years later in others. Its cumulative occurrence after thefirst year continues to rise with 0.5-2% annually, and it has been suggested that vir-tually all patients treated in this way will eventually become hypothyroid. Varioustreatment schedules have been devised with the hope of diminishing the incidence ofRAI-induced hypothyroidism 2,3, but in general, a lower incidence of hypothyroidismis invariably associated with a higher prevalence of persistent thyrotoxicosis that re-quires retreatment 3,4. Inadvertent administration of RAI during gestation may causeneonatal hypothyroidism when given to the mother during the last two trimestersand also occasionally in the first trimester of pregnancy 5. Hypothyroidism occursless often (6-13 %) after 131I treatment of toxic nodular goiter 6,7.

External irradiation. Hypothyroidism may supervene after therapeutic irradiation ofthe neck for any of a number of malignant diseases. It is particularly common (25-50%) after irradiation for Hodgkins’ and non-Hodgkins’ lymphoma, especially whenthe thyroid has not been shielded during mantle field irradiation and when iodine-containing X-ray contrast agents have been used prior to radiotherapy 8. Externalradiotherapy for head and neck cancer (e.g. laryngeal carcinoma) carries an actuarialrisk of 15% for developing overt hypothyroidism three years after treatment 10. El-evated TSH values are even more common, with a 5-year incidence rate of 48% inanother study with a median follow-up of 4,4 years 11 .

Total body irradiation with subsequent bone marrow transplantation for acuteleukemia or aplastic anemia may cause (subclinical) hypothyroidism in about 25%,usually occurring after one year and transient in half of the patients 9. Probablybecause of radiation damage, subclinical or overt hypothyroidism is commonamong surviving bone marrow transplant recipients. There is a greater risk amongyounger patients, and need for life-long surveillance.(J Clin Endocrinol Metab. 2004Dec;89(12):5981-6. Long-term follow-up of thyroid function in patients who receivedbone marrow transplantation during childhood and adolescence.Ishiguro H, YasudaY, Tomita Y, Shinagawa T, Shimizu T, Morimoto T, Hattori K,Matsumoto M, InoueH, Yabe H, Yabe M, Shinohara O, Kato S.)

9.3.5 INFILTRATIVE AND INFECTIOUS DISEASESThe production of hypothyroidism by infiltrative disease is mentioned for complete-ness, despite the rarity of these conditions. Among these rare causes of primary hy-pothyroidism are sarcoidosis, cystinosis 1(up to 86% in adults), progressive systemicsclerosis and amyloidosis 2. Hypothyroidism is a frequent sequela of invasive fibrousthyroiditis of Riedel, occurring in 30-40% of the patients.

Hypothyroidism due to infectious disease is equally rare. Infection of the thyroidgland is somewhat more frequent in immunocompromised patients and in subjectswith pre-existent thyroid abnormalities. Hypothyroidism in the recovery phase ofsubacute thyroiditis of De Quervain - a condition most likely related to a previousviral infection- is in contrast a very common event (see Ch. 19).

9.3.6 CONGENITAL HYPOTHYROIDISMCongenital hypothyroidism can be permanent or transient in nature. Transient casesmight be caused by transplacental passage of TSH receptor blocking antibodies, oriodine excess. Permanent cases are caused by either loss of functional tissue (mostly

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thyroid dysgenesis), by functional defects in thyroid hormone biosynthesis ( loss offunction’ mutations in genes encoding for the TSH-R, NIS, Tg, THOX or TPO), or bythyroid hormone resistance (TR mutations). For full discussion: see Ch. 15 and 16.

9.3.7 IODINE DEFICIENCY AND IODINE EXCESSHypothyroidism caused by iodine deficiency is discussed in Ch. 20. It is remarkablethat hypothyroidism can also be caused by iodine excess, a condition described inthe literature as iodide-induced myxedema’. It can be explained by autoregulatorymechanisms operative in the thyroid gland. Inorganic iodide in excess of daily dosesof 500-1000 µg inhibits organification of iodide; this phenomenon is known as theWolff-Chaikoff effect. Usually an escape from the Wolff-Chaikoff effect occurs afterseveral weeks. An unidentified iodinated product of the organification process (pre-sumably an iodinated lipid) seems to be involved, which inhibits thyroidal iodidetransport: consequently, the intrathyroidal iodine concentration falls below the levelrequired for inhibition of organification 1. Failure to escape from the Wolff-Chaikoffeffect may produce hypothyroidism and this occurs preferentially in subjects withpre-existent subtle organification defects. Indeed patients with chronic autoimmunethyroiditis, previous subacute or postpartum thyroiditis, or previous radioiodine orsurgical therapy are prone to iodide-induced hypothyroidism 2, 3.

Sources of iodine excess are an iodine-rich diet (e.g. seaweed ) and iodine-containingdrugs like potassium iodide, some vitamin preparations, kelp tablets, topical anti-septics, radiographic contrast agents, and amiodarone. Amiodarone contains 39% ofiodine by weight; large quantities of iodine are released during the biotransformationof the drug, giving rise to a 45-60 times higher iodine exposure than the optimal dailyiodine intake of 150-300 µg recommended by the WHO.

Amiodarone-induced hypothyroidism occurs predominantly in the first 18 months oftreatment, especially in females with pre-existent thyroid antibodies 4. Its incidence ishigher in regions with a high ambient iodine intake than in areas with a lower iodineintake (22% and 5% respectively) 5.

9.3.8 DRUG-INDUCED HYPOTHYROIDISMA variety of therapeutic drugs can lead to moderate or even severe hypothyroidism(see also Ch. 9.8.3). The common antithyroid drugs (carbimazole, methimazole, andpropylthiouracil) if given in sufficient quantity will cause hypothyroidism. This isalso theoretically possible with agents that can block the uptake of iodide by thethyroid, such as perchlorate or thiocyanate, although these are rarely given. In sus-ceptible individuals, primarily those with a history of autoimmune thyroid diseasesuch as Hashimoto’s or Graves’ disease or in patients who have had either radia-tion or surgical trauma to the thyroid gland, large doses of iodide can cause goitroushypothyroidism 1,2(see also Ch. 9.3.7). While this is now less common, since iodidesare no longer given for chronic pulmonary disease and lipid-soluble contrast agentsare no longer used in diagnostic procedures, the problem may arise with patientstaking iodine supplements or natural foods with high iodine content. Lithium hassimilar effects to those of iodide; it inhibits thyroid hormone release as well as hor-mone synthesis 3. While lithium-induced hypothyroidism is more common in pa-tients with underlying autoimmune disease, it has been reported in individuals withapparently normal thyroid glands. Long-term treatment with lithium results in goi-ter in about 50%, in subclinical hypothyroidism in about 20%, and in overt hypothy-roidism also in 20% 4. There are a large number of organic compounds that may im-pair thyroid function. These include phenol derivatives such as resorcinol, benzoicacid compounds such as para-aminosalicylic acid, the oral sulfonylurea compounds,phenylbutazone, aminoglutethimide, and a number of other agents 5. Industrial pol-lution with polychlorinated biphenyls can also cause goitrous hypothyroidism 6.

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9.3.9 MASSIVE INFANTILE HEMANGIOMASevere hypothyroidism has been described in a few infants with massive heman-giomas, due to high levels of activity of type 3 iodothyronine deiodinase in the he-mangioma tissue 1. Type 3 deiodinase inactivates T4 by conversion into reverse T3(explaining the paradoxically high serum rT3 concentrations in these hypothyroidpatients), and T3 by conversion into 3,3?-diiodothyronine. The high level of expres-sion of type 3 deiodinase is likely induced by gowth factors. The infants have noevidence of thyroid gland disease, and their hypothyroidism is apparently causedby an increased rate of thyroid hormone degradation in extra-thyroidal tissues out-stripping the rate of thyroid hormone production: a nice example of ?consumptive?hypothyroidism. This type of ?peripheral? hypothyroidism has also been observedin a young adult 3 . Surgical removal of the hemangioma restores euthyroidism.

9.4 PATHOLOGY OF HYPOTHYROIDISMThe characteristic pathologic finding in hypothyroidism is a peculiar mucinous non-pitting edema (myxedema), which is most obvious in the dermis but can be presentin many organs. The myxedema is due to accumulation of hyaluronic acid and otherglycosaminoglycans in interstitial tissue; these hydrophilic molecules attract muchwater 1. The deposits of glycosaminoglycans have been related to loss of the in-hibitory effects of thyroid hormone on the synthesis of hyaluronate, fibronectin andcollagen by fibroblasts 2,3.

The skin is distinctly abnormal. There is hyperkeratotic plugging of sweat glandsand hair follicles. The dermis is edematous, and the collagen fibers are separated,swollen, and frayed. Extracellular material that appears eosinophilic or basophilic inhematoxylin and eosin stains, or that appears pink (metachromatic) with toluidineblue, or takes the periodic acid-Schiff (PAS) stain for mucopolysaccharides is muchincreased in the dermis. A sparse mononuclear cell infiltrate may be found about theblood vessels.

Skeletal muscle cells are swollen and appear grossly to be pale and edematous. Fre-quently microscopic examination reveals no significant abnormality. Alternatively,the normal striations are lost, and degenerative foci are seen in the cells. The fibers areseparated in these degenerative foci by accumulations of a basophilic, PAS-positivehomogenous infiltrate. This infiltrate may appear as a semilunar deposit under thesarcolemma.

The heart may be dilated and hypertrophied. Interstitial edema and an increase infibrous tissue are present. The individual muscle cells may show the same changesseen in skeletal muscle. The serous cavities may all contain abnormal amounts offluid with a normal or high protein content. The liver may appear normal or mayshow evidence of edema. Central congestive fibrosis in the absence of congestiveheart failure has been described. The mitochondria tend to be spherical and their lim-iting membranes smooth, whereas those of the liver in thyrotoxicosis vary in shapeand have wrinkled outer membranes 4. The skeleton may be unusually dense on ra-diographic examination. In children, bone maturation is usually retarded, and typicalepiphyseal dysgenesis of hypothyroidism is present 5. The brain may show atrophy ofcells, gliosis, and foci of degeneration. Deposition of mucinous material and roundbodies containing glycogen (neural myxedematous bodies) has been found in thecerebellum of patients with long-standing myxedema and ataxia 6. In uncorrectedcongenital hypothyroidism , the brain retains infantile characteristics. There is neu-ronal hypoplasia, retarded myelination, and decreased vascularity (see Ch. 15). Theblood vessels often show prominent atherosclerosis. Whether this condition is moresevere than might be anticipated on the basis of the patient’s age and sex remains anunsettled question. In the intestinal tract there is an accumulation of mast cells andinterstitial mucoid material, especially near the basement membrane. The smoothmuscle cells may show lesions similar to those seen in skeletal muscle. The mucosaof the stomach, small bowel, and large bowel may be atrophic. The rest of the gas-

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trointestinal tract, especially the colon, may be very dilated (myxedema megacolon).The uterus typically has a proliferative or atrophic endometrium in premenopausalwomen.

The kidney is grossly normal. Light and electron microscopic studies of renal biopsysamples have demonstrated thickening of the glomerular and tubular basementmembranes, proliferation of the endothelial and mesangial cells, intracellularinclusions, and extracellular deposition of amorphous material with characteristicsof acid mucopolysaccharides 8,9.

In the pituitary in primary myxedema there is an increase in a class of cells that can beidentified by the iron-periodic, acid Schiff, or aldehyde fuchsin staining techniques 10.These are referred to variously as gamma cells, sparsely granulated basophils, or am-phophils. Presumably they are derived from basophilic cells or chromophobes andare active in secreting TSH. Acidophilic cells are decreased. Patients who are congen-itally hypothyroid and those who are hypothyroid during childhood may developpituitary fossa enlargement. Occasionally prolonged hypothyroidism leads to sellaenlargement in the adolescent and adult, and pituitary tumors have been described 11.In these glands acidophils are virtually absent. In pituitary hypothyroidism the pitu-itary may be replaced by fibrous and cystic structures, granulomas, or neoplasia. Oc-casionally hypothyroidism due to deficient TSH secretion occurs in patients havingthe empty sella syndrome or because of isolated TSH or TRH deficiency. The adrenalsmay be normal or their cortex may be atrophied. The combination of adrenal corticalatrophy and hypothyroidism is known as Schmidt’s syndrome and is thought to beof autoimmune etiology. Bloodworth found clinical evidence for hypothyroidism in9 of 35 patients with Addison’s disease; in 8 there was fibrosis of thethyroid, withatrophy in 4. The adrenal medulla appeared normal 12. The ovaries and parathyroidshave shown no definite abnormalities. The testes may show Leydig cells with involu-tionary nucleus and cytoplasm, hyalinization, or involution of the tubular cells, andproliferation of intertubular connective tissue in hypothyroidism with onset beforepuberty. Onset after maturity, in one case, led to similar changes that were restrictedto the tubules.

The pancreatic islets are usually normal, although hyperplasia was present in one ofour autopsied cases.

9.5 SYSTEMIC MANIFESTATIONS OF HYPOTHYROIDISMThe clinical expression of thyroid hormone deficiency varies considerably betweenindividuals, depending on the cause, duration and severity of the hypothyroid state.Characteristically, there is a slowing of physical and mental activity, and of manyorgan functions.

9.5.1 ENERGY AND NUTRIENT METABOLISMThyroid hormone deficiency slows metabolism, resulting in a decrease of resting en-ergy expenditure, oxygen consumption, and utilization of substrates. Reduced ther-mogenesis is related to the characteristic cold intolerance of hypothyroid patients.Measurement of the resting energy expenditure is rarely performed nowadays. Inpatients with complete athyreosis it falls between 35 and 45 percent below normal.In Addison’s disease, the BMR may fall to -25 or -30 percent and, in hypopituitarismto below - 50 percent. The failure to find a metabolic rate as low as - 35 percent, whenthe clear-cut picture of myxedema is present is very unusual. The effect of thyroidhormone deficiency on appetite and energy intake is not precisely known but energyexpenditure certainly decreases, leading to a slight net gain in energy stores. An in-crease of adipose tissue mass results in an increase of serum leptin, which mediatesa decrease in energy intake while energy disposal increases, eventually leading to areduction in adipose tissue mass. Interactions between leptin and thyroid hormonehave thus attracted much interest , especially because prolonged fasting in rodentsdecreases leptin and inhibits the hypothalamic-pituitary-thyroid axis resulting in a

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fall of serum TSH and serum T4. In hypothyroid patients, an increase, no change,or a decrease in plasma leptin concentrations has been reported. In one study, lep-tin concentrations expressed as standard deviation scores (Z-scores) from the meanvalue of female controls matched for body mass index and age, were lower in hy-pothyroid and higher in thyrotoxic women, whereas Z-scores did not deviate fromthe expected values after restoration of the euthyroid state 1. Thyroid hormone ap-parently modulates serum leptin to a small extent.

Protein metabolism. The effect of hypothyroidism on protein metabolism is complex,and its effect on the concentration of a given protein difficult to predict. In general,both the synthesis and the degradation of proteins are reduced, but hypothyroidpatients are in positive nitrogen balance. Despite both a decrease in the rate of al-bumin synthesis and degradation, the total exchangeable albumin pool increases inmyxedema 2. The albumin is distributed in a much larger volume, suggesting en-hanced permeability of capillary walls. A synthesis of thyroid hormone-responsiveproteins is clearly reduced in the hypothyroid state, whereas that of proteins such asTSH or glycosaminoglycans may be increased under the same circumstances 3,4.

Comparative studies of protein translation by hepatic ribosomes from T3-treatedhypothyroid rats show that the mRNA’s from some proteins are increased andothers are decreased. Most of these proteins have not been identified. Treatment ofmyxedema is accompanied by mobilization of extracellular protein and a markedbut temporary negative nitrogen balance, reflecting the mobilization of extracellularprotein 5. In a later phase there is an increase in urinary potassium and phosphorustogether with nitrogen in amounts suggesting that cellular protein is also beingmetabolized 6.

Carbohydrate metabolism. Glucose is absorbed from the intestine at a slower ratethan normal. Fasting plasma glucose values are on average lower than normal 7,8. Theoral glucose tolerance test usually produces a low peak value that remains elevatedat 2 hours. This response does not resemble that encountered in diabetes mellitus andis probably related to slow gastric motility and delayed absorption.

However, the glucose disappearance rate is also prolonged when the sugar is givenintravenously, although the peak value is normal in magnitude and in time of occur-rence 9. Insulin release in response to an oral glucose load may be variable due tothe absorptive abnormalities associated with hypothyroidism. The insulin responseto intravenous glucose is blunted and slightly delayed 9. In contrast to adult-onsetdiabetes, there is no evidence of resistance to insulin. In fact, the prolonged hypo-glycemic effect of exogenous insulin in hypothyroid patients suggests increased sen-sitivity to insulin action 8,10. This response, as well as the decrease in appetite, ac-counts for the diminished insulin requirement for the control of hypothyroid diabet-ics.

Lipid metabolism. Biosynthesis of fatty acids and lipolysis are reduced. Changes inserum lipids are listed in Table 9-4. The free fatty acid concentration is usually nor-mal, but can be higher than normal in some patients 23. The lipid changes bear ingeneral a reciprocal relationship to the level of thyroid activity.

The increased serum cholesterol may represent an alteration in a substrate steady-state level caused by a transient proportionally greater retardation in degradationthan in synthesis 11,12,13. The increase of serum cholesterol is largely accounted for byan increase of LDL-cholesterol, which is cleared less efficiently from the circulationdue to a decreased T3-dependent gene expressing of the hepatic LDL-receptor 14-16.

Table 4. Changes in serum lipids in hypothyroidism

Cholesterol LDL-cholesterol HDL2-cholesterol HDL 3-cholesteroltriglycerides

Increase increase (13-16) modestincrease (17-20) no change (17-20) nochange or modest increase

Interestingly, the LDL particles of hypothyroid patients are also susceptible to in-

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creased oxidizability 18. The increase of HDL2- but not of HDL3-cholesterol 18,19is dueto a diminished activity of cholesteryl ester transfer protein 20,21and hepatic lipase(which is involved in the conversion of HDL2 to HDL3). The changes in plasma LDL-and HDL-cholesterol are related to changes in free thyroxine, not to polymorphismsin LDL receptor or cholesteryl ester transfer protein genes 22. The sometimes presentmodest increase of serum triglycerides has been related to a decreased lipoprotein li-pase activity in post-heparin plasma. Lipoprotein(a) is increased in hypothyroidismin some but not all studies. Remnant particles in serum (reflecting chylomicron andVLDL remnants) are less effectively cleared in hypothyroidism 24,25 . Taken together,the changes in plasma lipids in hypothyroidism result in an atherogenic lipid profile26 .

9.5.2 FACIES AND INTEGUMENTIn the Report on Myxedema there is a detailed analysis of the symptoms of 109 pa-tients described as "cretinoid," "expressionless," "heavy," "apathetic," "masklike," "va-cant," "stolid," "good-tempered," "blunted," and "large-featured." The face is expres-sion less when at rest, but it is not masklike, as in Parkinson’s disease. When spokento, the person with myxedema usually responds with a smile, which spreads after alatent period very slowly over the face. The patient is good-tempered but not entirelyapathetic. The face is not vacant, as that of psychopathic patient may be. The features(except for the tongue) are not large, as in acromegaly. The face is expressionless atrest, puffy, pale, and often with a yellowish or old ivory tint. It is seldom as puffyas the classic facies of chronic renal failure. The skin of the face is parchment-like.In spite of the swelling it may be traced with fine wrinkles, particularly in pituitarymyxedema. The swelling sometimes gives it a round or moonlike appearance (Fig.9-3).

Figure 3. (A) The classic torpid facies of severe myxedema in a man. The face ap-pears puffy, and the eyelids are edematous. The skin is thickened and dry. (B) Thefacies in pituitary myxedema is often characterized by skin of normal thickness,covered by fine wrinkles. Puffiness is usually less than in primary myxedema. Theeyelids are often edematous. The palpebral fissure may be narrwowed becauseof blepharoptosis, due to diminished tone of the sympathetic nervous fibers toMüller’s levator palpebral superious muscle and is the opposite of the lid retrac-tion seen in thyrotoxicosis. The modest measurable exophthalmos seen in some

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patients with myxedema is presumably related to accumulation of the same mu-cous edema in the orbit as is seen elsewhere. It is not progressive and carries nothreat to vision, as in the ophthalmopathy of Graves’ disease. The tongue is usu-ally large, occasionally to the point of clumsiness. Sometimes a patient will com-plain of this problem. Sometimes it is smooth, as in pernicious anemia (of course,pernicious anemia may coexist). Patients do not usually complain of soreness ofthe tongue, as they may in pernicious anemia. When anemia is marked, the tonguemay be pale, but more often it is red, in contrast to the pallid face.

The voice is husky, low-pitched, and coarse. The speech is deliberate and slow. Of-ten there is difficulty in articulation. Certain words are stumbled over and slurred,much as they are during alcoholic intoxication. The enlargement of the tongue, andpossibly some thickness of the lips, may be responsible. The hair, both of the headand elsewhere, is dry, brittle, and sparse, and lacks shine. It varies in texture fromcoarse to normal. Its growth is retarded and it falls out readily. The eyebrows oftenare practically gone. Their disappearance begins at the lateral margin, giving rise toQueen Anne’s sign. It should be noted, however, that this sign is not uncommon inelderly euthyroid women. In men the beard becomes sparse, and its rate of growthbecomes greatly retarded. Haircuts are necessary only at long intervals. A shave aweek is sufficient. The scalp is dry and scaly. The skin is cool as a result of decreasedmetabolism as well as cutaneous vasoconstriction. It is dry due to reduced secretionby sweat and sebaceous glands.

Scaling is common but rarely assumes the appearance characteristic of ichthyosis.The tissues beneath it seem thick, but usually do not pit on pressure. In the lower ex-tremities, pitting edema is not uncommon. Subcutaneous fat may be increased, withthe formation of definite fat pads, especially above the clavicles, but is conspicuouslyabsent in the more advanced form of the disease (myxedematous cachexia).

Retardation in the rate of healing of surgical wounds and of ulcerations, such as legulcers, has been described in myxedema. The nails are thickened and brittle. Thesechanges are probably dependent, as are those of skin and hair, on retardation ingrowth. Nails require paring only at greatly lengthened intervals.

The hands and feet have a broad appearance, due to thickening of subcutaneoustissue. However, there is no bony overgrowth, so that they bear no resemblance tothe extremities in acromegaly. Unusual coldness of the arms and legs is sometimesa subject of complaint. The palms are cool and dry. The characteristic skin changesare due to an increased amount of normal glycosaminoglycans and protein. The gly-cosaminoglycans are demonstrated by metachromasia after staining with toluidineblue. An increased concentration of glycosaminoglycans, composed principally ofhyaluronic acid and chondroitin sulfuric acid, occurs in histologically similar skin le-sions found in hyperthyroidism (pretibial myxedema). This excess accumulation ofnormal intercellular material represents not only an alteration in steady-state equilib-rium but an actual increase in the synthesis and accumulation of glycosaminoglycan1.

The glycosaminoglycans are long-chain polymers of D-glucuronic acid andN-acetyl-D-glucosamine, forming hyaluronic acid, or of L-iduronic acid andN-acetyl-D-galactosamine sulfate, forming chondroitin sulfate B. They exist freeand in ionic or covalent linkage to protein. These mucoproteins comprise part ofthe normal nonfibrillar intercellular matrix, the ground substance holding cellstogether. As they are characteristically hygroscopic, they presumably hold in boundform the nonpitting water comprising the mucous edema. The total amount ofexchangeable sodium is increased in myxedema despite a slight reduction in itsplasma concentration 2.

The sodium is extravascular and probably in the interstitial spaces. The diuresis seenafter giving thyroid hormone to a hypothyroid subject occurs coincidentally with adecrease in tissue metachromasia and a temporary negative nitrogen balance 3, andwith this condition the extravascular sodium is mobilized and excreted. Studies withhuman skin fibroblasts have suggested that thyroid hormone inhibits the synthesis

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of hyaluronate. The mechanism for this effect has not been identified, but the thy-roid hormone levels required to produce it in vitro are in the physiologic range 1,4.Although similar deposits of mucopolysaccharides are found in the orbits of patientswith the ophthalmopathy of Graves’ disease and in the areas of localized myxedema,this striking observation has unfortunately not provided any basic understanding ofthe phenomenon, either in this condition or in primary myxedema.

9.5.3 NERVOUS SYSTEMRecent studies using 32P nuclear magnetic resonance spectroscopy of the frontal lobeof adult hypothyroid patients report reversible alterations in phosphate metabolism,suggesting impairment of mitochondrial metabolism 1. Thyroid hormone receptorsare present in human brain. These and other findings indicate the adult human brainas a thyroid hormone responsive organ, and provide a biologic basis for the veryprevalent neurologic and neurobehavioral symptoms in adult hypothyroid patients2(Table 9-5).

Table 5. Neurologic and psychiatric manifestations of hypothyroidism.

Neurologic Symptoms or signs Headache Paresthesias Carpal tunnel syndromeCerebellar ataxia Deafness: nerve or conduction type Vertigo or tinnitus Delayedrelaxation of deep tendon reflexes Cognitive deficits: calculation, memory, reducedattention span Low-amplitude theta and delta waves on EEG Prolonged evokedpotentials Sleep apnea Myxedema coma Elevated CSF protein concentrationPsychiatric syndromes Depression: akinetic or agitated Schizoid or affectivepsychoses Biopolar disorders

Table 9-5 lists the numerous symptoms suggesting either neurologic or psychiatricdisorders in patients with moderate to severe hypothyroidism. We are aware of nocharacteristic motor phenomena other than those due to weakness and to syndromesthat seem to represent cerebellar dysfunction. A tendency to poor coordination wasnoted originally by the Myxoedema Commission. Jellinek and Kelly 3described a se-ries of myxedematous patients with ataxia, intention tremor, nystagmus, and dysdi-adochokinesia. Ataxia has been noted in 8 percent of a large series of hypothyroidpatients 4. The delayed relaxation phase of the deep tendon reflexes is a well-knownmanifestation. Patients may have intention tremor, nystagmus, and an inability tomake rapid alternating movements. In fact, this inability has long been used as a testfor myxedema. The cause of this syndrome is not apparent, although deposition ofmucinous material in the cerebellar tissue may be of pathogenetic importance. What-ever the cause is, it is important that these symptoms show a prompt and definitedecrease after replacement therapy with thyroid hormone 5.

Sensory phenomena are common. Numbness, tingling, and painful paresthesias arefrequent 6and are especially common in hypothyroidism after surgery or 131I ther-apy. Paresthesias were present in 79 percent of one series of 109 patients. A metachro-matic infiltrate has been found in the lateral femoral cutaneous nerve and sural nerve,together with axon cylinder degeneration 7. Nerve conduction time is usually nor-mal. Murray and Simpson 8found that in some hypothyroid patients signs of mediannerve pressure were present, apparently because of encroachment on the nerve bymyxedematous infiltrates in the carpal tunnel 9,10. A recent study reports carpal tunnelsyndrome in 29% and signs of sensorimotor axonal neuropathy in 42% 22. Deafness isa very characteristic and troublesome symptom of hypothyroidism. Both nerve andconduction deafness and combinations of the two have been reported, and vestibu-lar abnormalities have also been demonstrated. Serous otitis media is not uncom-mon. Two-thirds of patients complain of dizziness, vertigo, or tinnitus occasionally:these problems again suggest damage to the eighth nerve or labyrinth, or possibly tothe cerebellum. Whatever type of deafness is present, there is marked improvementafter thyroid therapy. Acute thyroxine depletion caused by total thyroidectomy has

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no deleterious effects on hearing up to 6 weeks 11. Acquired hearing loss in associa-tion with adult-onset hypothyroidism should be distinguished from the sensorineu-ral deafness of Pendred’s syndrome. In the latter, treatment of hypothyroidism doesnot correct the hearing defect.

Night blindness is not uncommon. It is caused by a deficiency in the pigmentretinene, which is required for the adaptation to dark. Uncorrected deficiencyof thyroid hormone during neonatal life causes not only more profoundneurologic abnormalities but also irreversible damage (see Ch. 15). Hashimoto?sencephalopathy is a vaguely defined condition in which otherwise unexplainedneurological manifestations of central nervous system dysfunction are linked toTPO-antibodies. The condition responds to glucocorticoids, but a causal relationto thyroid autoimmunity is unproven 26 . Mental Symptoms. The mental pictureusually is one of extreme complacency. Memory is undoubtedly impaired, andattention and the desire to think are reduced . The emotional level seems definitelylow, and irritability is decreased. Except in the terminal stage, reasoning poweris preserved. Questions are answered intelligently, but slowly and withoutenthusiasm, and often with evidence of amusement. In a minority of patients,nervousness and apprehension are present. Psychosis may occur in untreatedmyxedema or during the initiation of therapy. This problem is discussed below.

Depression is so often associated with hypothyroidism that thyroid function testsshould be performed in the evaluation of any patient presenting with this symptom.Central 5-hydroxytryptamine activity is reduced in hypothyroid patients 12, and T3supplementation might increase the efficacy of antidepressant drugs 13. At times, thismanifestation of hypothyroidism is more severe than are many of the other clini-cal manifestations of the disease. Because hypothyroidism is so readily treated, it isan especially important cause to eliminate. Cognitive tests of patients with moder-ate to severe hypothyroidism indicate difficulties in performing calculations, recentmemory loss, reduced attention span, and slow reaction time 14,27. Failing memorycorrelates inversely with serum T3 and T4 23. Hypothyroidism may give rise rarelyto reversible dementia, associated with reversible cerebral hypoperfusion 24. EEG ab-normalities are also present, again depending on the severity and duration of the hy-pothyroidism. There may be absence of a waves and presence of low-amplitude thetaand delta waves. Visual and auditory evoked potentials may be delayed as a conse-quence of abnormal cerebral cortical metabolism. Sleep apnea is not uncommon 15. Ithas been difficult to assign a causal role for the myopathy versus the coexistent obe-sity in some of the reported cases. However, the muscular dysfunction may extend tothe diaphragm and intercostal muscles, thus impairing the ventilatory mechanism.

The most extreme CNS manifestation of hypothyroidism is myxedema coma (see §9.9). The typical somnolence of severe hypothyroidism may suggest the psychiatricdiagnosis of depression or dementia 16. Patients are generally akinetic, though iso-lated case reports appear of patients who become hypomanic and agitated or garru-lous (myxedema wit) as manifestations of this condition. Bipolar affective disordersand schizoid or paranoid ideations may also occur. These may so dominant the clin-ical picture that the signs of hypothyroidism may be obscured or pass unnoticed.Accordingly, it is critical to evaluate thyroid function in any patient presenting withsuch functional disorders before instituting other forms of therapy. If the condition isdue to hypothyroidism, it will resolve with time and appropriate treatment 17,18.

Cerebral blood flow, oxygen consumption, and glucose consumption have been re-ported to be diminished in proportion to the drop in metabolism in the rest of thebody 19, but older studies found unaltered glucose and oxygen use by the brain ineither hypo- or hyperthyroid animals or humans 20. In one study, cerebral corticalperfusion was little changed with treatment, but there was a decided fall in cere-brovascular resistance 21. Recent studies indicate a generalized decrease in regionalcerebral blood flow of 24% and in cerebral glucose metabolism of 12%, indicatingthat brain activity is globally reduced in severe hypothyroidism without the regionalmodifications usually observed in primary depression 25.

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9.5.4 CARDIOVASCULAR SYSTEM

Table 8. Gastrointestinal manifestations of hypothyroidism.

Symptoms• anorexia

• gaseous distention

• constipation

Signs• prolonged gastric emptying

• prolonged intestinal transit time

• slowed intestinal absorption

• rarely ileus or ascites

• elevated liver enzymes and CEA

• gallbladder hypotonia

Pulse rate and stroke volume are diminished in hypothyroidism, and cardiac out-put is accordingly decreased, often to one-half the normal value 1. Myocardial con-tractility is reduced, but there is also a steep decline in the circulatory load, so thatthe circulation rarely fails until very late in the disease 2. The speed of shortening isslowed, but the total force is not much modified. 3. Myocardial adenyl cyclase levelsare reduced 4. The decrease in pulse rate occurs more or less in parallel with that ofthe metabolism. Stroke volume is reduced more than pulse rate at any given level,and is therefore the major determinant of the low cardiac output. Since the reductionin cardiac output is usually proportional to the decreased oxygen consumption bythe tissues, the arteriovenous (AV) oxygen difference is normal or may be slightlyincreased. Slow peripheral circulation, and therefore more complete extraction ofoxygen, as well as anemia, may be responsible for the increased AV oxygen differ-ence. Myocardial oxygen consumption is decreased, usually more than blood supplyto the myocardium, so that angina is infrequent. In some patients a reduction in car-diac output greater than the decline in oxygen consumption indicates specific cardiacdamage from the myxedema 5.

Venous pressure is normal, but peripheral resistance is increased. Restoration of theeuthyroid state normalizes peripheral vascular resistance. Changes in peripheral vas-cular resistance are not related to plasma adrenomedullin, but altered atrial natri-uretic peptide secretion and adrenergic tone may contribute 29. Central arterial stiff-ness is increased in hypothyroidism 30 , and arterial blood pressure is often mildlyincreased. It varies widely, but diastolic hypertension is usually restored to normal af-ter treatment 6,7,31. The heart in hypothyroidism has been a focus of much controversy.The term Myxodemherz was introduced by Zondek in 1918 8. It embraced dilatationof the left and right sides of the heart, slow, indolent heart action with normal bloodpressure, and lowering of the P and T waves of the electrocardiogram. Zondek foundthat after treatment with thyroid hormone there was a return of the dilated heart tosomewhere near normal size, a more rapid pulse without change in blood pressure,and gradual return of the P and T waves to normal. These findings have been con-firmed and extended. Indeed, occasional severely hypothyroid patients without un-derlying heart disease have congestive heart failure or low cardiac output reversedby thyroid hormone administration 7,9,10. Therefore, congestive heart failure or im-paired cardiac output relative to metabolic needs can be caused by hypothyroidism.

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Microscopic examination discloses myxedematous changes of the myocardial fibers.

The cause of the cardiac enlargement has been disputed. Clearly, it is not due to hy-pertrophy alone, since it would not disappear so rapidly with treatment. One factormay be a decrease in contractility of the heart muscle. This decrease would require alengthening of muscle fibers in order to perform the required work. Disappearance ofinterstitial fluid alone could account for only part of the observed schrinkage. Alteredmyosin synthesis is also important.

Gordon 11long ago called attention to the occurrence of pericardial effusion inmyxedema and explained the increase in the transverse diameter of the heartshadow on this basis. Effusion must frequently play a role in the increase in thesize of the heart shadow, but it has amazingly little effect on cardiodynamics. Thepresence of fluid may be reflected in the right ventricular pressure contour, buttamponade, although reported, is rare 12,13. Effusions of the pericardium, pleura,and peritoneum are common findings in hypothyroidism 14. The protein of theeffusion may be high or in the range of transudates. In 11 patients with tamponadestudied, pericardial fluid protein ranged from 2.2 to 7.6 g/dl 12. Occasionally, thefluid is high in cholesterol, with a "gold paint" appearance 13. The hypothyroid heartresponds normally to exercise 5,7. Graettinger et al. 1found that after exercise the lowresting cardiac output increased normally with an increase of stroke volume andusually, of pulse rate. Their patients had slightly elevated resting pulmonary arteryand right ventricular pressures and a diastolic dip in right ventricular pressure,all compatible with pericardial effusion. They doubt that myxedema alone canever produce congestive heart failure, and believe that the recorded abnormalitiesrepresent not myocardial disease but pericardial effusion. The heart, in experimentalhypothyroidism, also responds to norepinephrine with a rise in cAMP, but less sothan does the normal heart, although the response in contractility is the same.

Plasma catecholamines in hypothyroid patients are elevated rather than reduced,even though circulating cyclic AMP is lower 7. This may be explained by a decreasein cyclic AMP generation in response to catecholamines only in certain tissues. Thereis a decrease in the number of ß-adrenergic receptors in the myocardium of hypothy-roid rats, but there are no data with respect to human myocardium.

Since the treatment of myxedema restores the hypothyroid heart to normal, there isapparently little permanent structural damage 9,10. Cardiac glycosides will not im-prove the function of the heart in uncomplicated myxedema. Although the drug isefficacious if heart failure has been produced by coincident organic disease, myxede-matous patients with coincident heart disease and congestive heart failure may tol-erated digoxin poorly, just as they do morphine. This poor tolerance probably repre-sents delayed metabolism, rather than myocardial sensitivity to the drug. The plasmaconcentration of digoxin is higher than in the normal subject at the same dose level,and smaller doses are required. When the heart in myxedema does not return to anormal size under thyroid hormone administration, hypertrophy due to some otherdisease is present as a complication. The return in size to normal under treatmentis slow and progressive, requiring between 3 weeks and 10 months for completion.This decrease in size, like the progressive elevation of the T waves (described below),is of diagnostic value.

The electrocardiogram reveals characteristic changes 5,7,10,15-19. The rate is slow and thevoltage is low. The T waves are flattened or inverted. Axis deviation, an increased P-Rinterval, and widened QRS complexes and prolonged QT interval are seen, but thesesigns are not diagnostic of myxedema. The pattern reverts toward normal with treat-ment, but the final pattern depends on the presence or absence of intrinsic myocardialdisease. The rare occurrence of complete heart block complicated by Adams-Stokesattacks, with reversion to sinus rhythm after treatment with thyroid hormone, hasbeen reported as has ventricular tachycardia 18,19.

Changes resembling those of ischemic heart disease may be found during exercise:they may indicate an intrinsic anoxia rather than organic narrowing of the coronaryvessels 5,7,10,17.

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The ECG changes have usually been attributed to the histologic changes in the my-ocardium. However, removal of pericardial fluid may immediately reverse the pat-tern toward normal suggesting that the effusion may in part be responsible for theabnormalities.

The systolic time intervals are prolonged in hypothyroidism 5,7,10,20. They can be mea-sured by several techniques and have been expressed as the ratio of the pre-jectionperiod and the left ventricular ejection time or the interval between the onset of theQRS complex of the ECG and the onset of the Korotkoff sound 21,22. The most obviouseffect of thyroid hormone deficiency on the heart is a lengthening of both systolic andearly diastolic time characteristics. As evaluated by equilibrium radionuclide angiog-raphy, the time to peak emptying rate and the time to peak filling rate are longer inhypothyroid patients than in controls 23; the time intervals are negatively related toserum FT4 in the hypothyroid patients. The subtle decrease in early active relaxationand prolongation of contraction without major changes in global systolic function ofhypothyroid patients is reversible upon thyroid hormone replacement therapy 24.

It is frequently suggested that accelerated atherosclerosis occurs in hypothyroidism32 . Hypothyroidism accelerates atheromatous changes when these are induced ex-

perimentally in animals, but data in humans are not complete enough to justify thisassertion. Most autopsied myxedematous subjects have severe atherosclerosis, butthey are also usually 60 years or more of age. Arterial disease did not appear tobe accelerated in patients rendered hypothyroid for therapy of angina pectoris orcongestive heart failure 22, but they have been observed over a relatively short pe-riod. Increased coronary arteriosclerosis is found in myxedematous patients withhypertension, but not if they are normotensive 25(see further §9.8.4). Nevertheless,the atherogenic profile of serum lipids and increased levels of homocysteine in hy-pothyroidism might well contribute to a higher prevalence of atherosclerosis in hy-pothyroid patients. However, a 20-year follow-up study in the UK did not observea higher incidence of ischemic heart disease in subjects with thyroid antibodies orhypothyroidism 35 . Another population-based study from The Netherlands, in con-trast, found subclinical hypothyroidism to be an independet risk factor for aorticatherosclerosis and myocardial infarction; the attributable risk was comparable tothat of other known risk factors for coronary artery disease 36 .

Occasionally angina pectoris is encountered in myxedema under two sets of circum-stances. The less common is that in which angina or angina-like pain is present beforetreatment 26,27,28. This generally indicates the presence of significant coronary arterycompromise since there is inadequate myocardial oxygenation despite reduced car-diac output and O2 utilization. Although improvement sometimes occurs with ther-apy 27, this should not be undertaken until angiographic evaluation of the coronaryarteries has been performed (see below).

Angina may also appear for the first time after therapy has been initiated, indicatingthat coronary flow is inadequate for resumption of normal cardiac function 26,27,28.Again, this may indicate the presence of a structural lesion.

9.5.5 RESPIRATORY SYSTEMDyspnea is a frequent complaint of myxedematous patients, but it is also a commonsymptom among well persons. Congestive heart failure of separate origin, pleural ef-fusion, anemia, obesity, or pulmonary disease may be responsible. Some informationon pulmonary function in hypothyroidism is available 1-7. Wilson and Bedell 1founda normal vital capacity and arterial PCO2 and PO2 in 16 patients. They also found adecreased maximal breathing capacity, decreased diffusion capacity, and decreasedventilatory response to carbon dioxide. Decreased ventilatory drive is present inabout one-third of hypothyroid patients, and the response to hypoxia returns rapidlywithin a week after beginning therapy 6.

The severity of hypothyroidism parallels the incidence of impaired ventilatory drive.Weakness of the respiratory muscles has also been implicated as a cause of alveo-

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lar hypoventilation. Patients with myxedema may develop carbon dioxide retention,and carbon dioxide narcosis may be a cause of myxedema coma 3,4.

Myxedematous patients are more subject to respiratory infections. Obstructive sleepapnea has been documented in hypothyroidism in about 7% and is reversible withtherapy 5,7. The prevalence of hypothyroidism in patients seen for snoring or obstruc-tive sleep apnea syndrome is, however, no greater than that seen in the general pop-ulation 8. The same authors report little or no improvement in apnea symptoms uponthyroid hormone replacement therapy in the hypothyroid patients.

9.5.6 MUSCULOSKELETAL SYSTEMMuscles.Muscle symptoms like myalgia, muscle weakness, stiffness, cramps andeasy fatiguability are very prevalent in hypothyroid patients 23,24 . Weakness inone or more muscles groups is present in 38% as evident from manual musclestrength testing 22.The symptoms are aggravated by exposure to cold. They arealso prominent during the rapid onset of hypothyroidism after surgery or 131Itherapy. Impairment of mitochondrial oxidative metabolism provides a biochemicalsubstrate for these complaints, as evident from a rise in the ratio of inorganicphosphate to ATP in resting muscle and an important decrease in phosphocreatinein working hypothyroid muscle with a greater fall in intracellular pH than incontrols 1,2. Transition from fast type II to slow type I muscle fibers is involved in thechange of muscle bioenergetics 3, which is probably multifactorial. One patientwith disabling muscle cramps was found to have reduced a-glucosidase activityin a muscle biopsy; after therapy with T4, the symptoms disappeared and themuscle enzyme activity returned to normal 4. The electromyogram in myxedemamay be normal or may demonstrate abnormalities distinct from those seen inmyotonia or other muscle disease 5. Polyphasic action potentials, hyperirritability,repetitive discharge, and low-voltage, short-duration motor unit potentials havebeen described. In the hypothyroid rat the rate of isometric relaxation is slow, andtension is less than in euthyroid or hypothyroid rat muscle at the same frequency ofstimulation.

Generalized muscular hypertrophy, accompanied by easy fatigue and slowness ofmovements, occurs in some cretins and myxedematous children or adults. It hasbeen referred to as the Kocher-Debré-Sémélaigne syndrome in children 6and as Hoff-mann’s syndrome in adults 7. These patients do not have the classic electromyo-graphic findings of myotonia. The myopathy of hypothyroidism is in some patientsassociated with weakness even though the muscles are hypertrophied.

Chronic hypothyroid myopathy with increased muscular volume rarely cause en-trapment syndromes 8. Reflex contraction and relaxation time is prolonged mainlybecause of the intrinsic alterations in muscle contractility. Nerve conduction timemay also be prolonged. Delayed reflex relaxation is characteristic and has been devel-oped into a diagnostic test of thyroid function 9. As with many other peripheral tissuefunction tests, there is considerable overlap between normal and mildly hypothyroidranges. The rate-limiting step in muscle relaxation is the reuptake of calcium by thesarcoplasmic reticulum. In skeletal muscle, this process is dependent on the contentof calcium ATPase. Recent studies have indicated that calcium ATPase activity of thefast twitch variety (SERCA-1) is markedly reduced in hypothyroidism 10, and there isan accompanying impairment of calcium reuptake as a consequence. This occurs at atranscriptional level, since thyroid hormone response elements have been identifiedin the 5’ flanking region of the SERCA-1 calcium ATPase gene 11. The reduction incalcium ATPase would appear to explain one of the most obvious clinical manifesta-tions of hypothyroidism, namely, delayed relaxation of the deep tendon reflexes.

Table 7. Manifestations of hypothyroidism in the musculoskeletal system.

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Clinical Symptoms and SignsMyalgia, muscle weakness, stiffness, cramps, fatigue Arthralgias joint stiffnessJoint effusions and pseudogout Carpal tunnel syndrome Delayed linear bonegrowth in children

LaboratoryNormal ionized calcium, phosphate, and bone density Increased serum PTH, 1 25(OH) 2-vitamin D 3Normal 25-OH vitamin D 3Reduced urine calcium, hydroxypro-line, serum alkaline phosphatase, osteocalcin, and IGF-1 Epiphyseal dysgenesis ordelayed ossification in children

Joints. At the clinical level, patients with hypothyroidism may present with manymanifestations, suggesting rheumatic disease such as arthralgias, joint stiffness,effusions, and carpal tunnel syndrome 12,13. On the other hand, the symptoms mayalso suggest polymyalgia rheumatica, or primary myositis. The similarity of thesymptoms of hypothyroidism to those of rheumatoid arthritis or osteoarthritis,especially when these are combined with the paresthesias of more severehypothyroidism, should automatically lead to a consideration of hypothyroidism inany patient presenting with these symptoms. For example, in 5 to 10 percent ofpatients with carpal tunnel syndrome, primary hypothyroidism may be the cause,due to the accumulation of the hygroscopic glycosaminoglycan in the interstitialspace with compression of the median nerve. Bones. While calcium, phosphate, andbone density are generally normal in hypothyroidism, there is evidence of reducedbone turnover and resistance to the action of parathyroid hormone (PTH) 14-21. Thus,serum (PTH) levels are elevated 16. This is presumably the cause of the elevationin 1a, 25(OH)2-vitamin D3 19. 25-OH-vitamin D3 levels are normal. The increasein PTH and vitamin D in turn increases calcium absorption. The reduction inglomerular filtration rate (GFR) and reduced bone turnover reduce urinary calciumand hydroxyproline levels and cause subnormal alkaline phosphatase, osteocalcin,and IGF-1 levels 15. The alkaline phosphatase reduction is particularly important inchildren, in whom this enzyme is normally elevated due to bone growth. In childrendelayed linear growth or short stature are well-recognized signs suggesting thepossibility of hypothyroidism. In addition, it is well recognized that epiphysealdysgenesis and the delayed appearance of calcification centers are characteristic ofhypothyroidism in infants and children. This subject is discussed in greater detail inChapter 15.

9.5.7 GASTROINTESTINAL SYSTEMThe symptoms from the digestive system are essentially the expression of the slowrate at which the living machinery is turning over. Anorexia, which is common, canreasonably be interpreted as the reflection of a lowered food requirement, and con-stipation, which is frequently present, is the result of a lowered food intake and de-creased peristaltic activity. Although two-third of patients have reported weight gain,it is modest degree and due largely to the accumulation of fluid rather than fat. Con-trary to popular belief, obesity is decidedly not a feature of hypothyroidism.

Complete achlorhydria occurs in more than half of myxedematous patients 1. Asmany as 25 percent of patients with myxedema, like those with Hashimoto’s thy-roiditis, have circulating antibodies directed against the gastric parietal cells. Thisfinding explains, at least in part, the frequency of achlorhydria and impaired absorp-tion of vitamin B12 described later. It is reported that up to 14 percent of patients withidiopathic myxedema have coincident pernicious anemia 2.

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Gastric emptying and intestinal transit time are prolonged 3. Gaseous distention maybe a persistent and troublesome symptom. It responds slowly to thyroid therapy.Fecal impaction may occur. The syndrome of ileus may be seen occasionally 4and amegacolon may be evident on radiography 5,6. Intestinal absorption is slowed.

Galactose and glucose tolerance curves show a delayed rise to a lower peak than nor-mal and a delayed retunr to baseline. Xylose absorption is impaired 7. Myxedematousascites is rare 8.

Symptoms or signs of disturbed liver or exocrine pancreatic function are usuallynot encountered, but chemical examination may suggest disease. Serum glutamine-oxaloacetic transaminase (GOT), lactate dehydrogenase (LDH), and CPK levels areelevated in patients with hypothyroidism 9 ,12 . The enzymes return to normal over 2to 4 weeks during treatment. Urinary amylase levels may be increased. CEA levelsare also increased and drop with therapy 8,10Gallbladder motility is decreased, andthe gallbladder may appear distended on x-ray examination 11.

9.5.8 RENAL FUNCTION, WATER AND ELECTROLYTESHypothyroid patients tend to drink small amounts of water and to have diminishedurinary output. Clinical evidence of renal failure is not often found, but laboratoryexamination may disclose certain departures from normal renal function; serum cre-atinine is raised by 10-20% 1. Because of decreased cardiac output and blood volume,renal blood flow is decreased, but it remains the same percentage of cardiac output.The glomerular filtration rate and effective renal plasma flow are decreased, but thefiltration fraction is normal or variably altered 2,3,4.

The response to water loading is variable. Moses et al. 5reported that deficient diure-sis after water loading is a sign of pituitary myxedema, but others, notably Crispelland co-workers 6have found that severe primary myxedema may be associated witha delay excretion that is not corrected by cortisone but rather by replacement withthyroid hormone. Perhaps the difference in opinion arises from interpretation of thenormal response to water loading. This possibility is suggested by the data of Bleiferet al. 7, who found a decrease in maximal diuresis in some patients with primarymyxedema to below the normal lower limit of urine flow (3 ml/min), but not downto the 1 to 3 ml/min seen in panhypopituitarisn. The role of antidiuretic hormoneand of solute excretion in producing the decreased response to water loading is un-known. The defect is usually attributed to a decreased glomerular filtration rate, butin some patients inappropriately high levels of serum vasopressin have been demon-strated 8-12. Since urinary hydroxycorticoid excretion is decreased, the adrenals mightbe incriminated as responsible for delayed water excretion. Other evidence, how-ever, suggests (see below) that the tissue supply of adrenal cortical hormones is usu-ally normal in myxedema. The diminished free water clearance in hypothyroidismoccurs irrespective of the presence of hyponatremia. The inappropriate antiduresisin hypothyroidism is thus not fully understood; a pure renal mechanism might beinvolved, independent of vasopressin 18 .

Occasionally, minimal proteinuria is seen. This condition could be due to congestiveheart failure or to the increased capillary transudation of protein typical of hypothy-roidism.

The total body sodium content is increased. The excessive sodium is presumablybound to extracellular mucopolysaccharides. In spite of reduced renal blood flowand blood volume, the sodium retention is probably not a reflection of altered renalfunction. In fact, salt loads are usually excreted readily and serum sodium concentra-tions tend to be low 13, in contrast to other clinical situations associated with sodiumretention, such as congestive heart failure 8. The dilutional syndrome may be a resultof inappropriate secretion of ADH 9-12, but not in all patients. Thus, the dilutional syn-drome in severe myxedema may be due to a resetting of the osmolar receptor, whichcauses water to be retained at a lower level of plasma osmotic pressure. The vari-ous changes in renal function may not return to normal at the same rate after treat-

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ment. The serum uric acid level is elevated in hypothyroid men and postmenopausalwomen, apparently as a consequence of a decrease in renal blood flow characteristicof the disease 14. No consistent changes in plasma potassium levels have been re-ported. Total magnesium levels may be elevated and the bound fraction and urinaryexcretion are reduced 15. A modest hypocalcemia has been observed in some patients.The significance of low ANF concentrations in hypothyroidism is presently unclear16.

Plasma homocysteine concentrations are increased in hypothyroidism, related tolower folate levels and a lower creatinine clearance in thyroid hormone deficiency;restoration of the euthyroid state decreases plasma homocysteine levels into thenormal range 1,17.

9.5.9 REPRODUCTIVE FUNCTIONIn both sexes libido is usually, but not invariably decreased. The man may be im-potent. The testicles are histologically immature if hypothyroidism preceded pu-berty and show tubular involution if onset was after puberty 1. In adult hypothy-roid men, semen analysis is usually normal. Although infertility may be a problemin either sex, the literature contains many reports of pregnancy in untreated myxede-matous women 2,3. When treatment has been started during pregnancy, more oftenthan not a normal child is produced, but abortion is frequent in the myxedematouswoman. Pregnancy-induced hypertension is 2 to 3 times more common in hypothy-roid women 4; low birth weight is secondary to premature delivery for gestational hy-pertension. The incidence of various congenital abnormalities may be increased, butrecent studies do not report an increased risk of fetal death or congenital anomalieswith proper treatment 2-7. The prevalence of an elevated serum TSH among pregnantwomen is in the order of 2% 21 . Mothers not receiving adequate L-thyroxine treat-ment have a higher abortion rate 22 , and the IQs of their children are 7 points lowerthan the IQs of control children 23 . In adult premenopausal hypothyroid women,77% have regular cycles and 23% irregular periods; corresponding figures in con-trols are 92% and 8% respectively 8. Oligomenoerhoea and menorrahgia are the mostcommon menstrual disturbances, which tend to be more frequent in severe hypothy-roid patients. Menorrhagia is sufficiently impressive in ordinary myxedema 9so thatin several cases that have come to our attention, patients have actually had dilata-tion and curettage or hysterectomy for it, the diagnosis of myxedema having beenmissed. The endometrium in premenopausal patients is typically proliferative or, lesscommonly, atrophic. The proliferative endometrium and low urinary pregnanetriollevels suggest failure of luteinizing hormone (LH) production and of ovulation 10. In-deed the pulsatile gonadotropin release in the follicular phase is normal 11, but theovulatory surge may not happen. In some patients, amenorrhea rather than menor-rhagia occurs, with a reinstitution of a normal menstrual pattern after therapy. Al-though less frequent, amenorrhea and galactorrhea are occasionally found in adulthypothyroidism due to hyperprolactinemia and are reversible with treatment 12. Inchildren, hypothyroidism sometimes induces precocious puberty with menstruationand breast development 13. On rare occasions, precocious testicular enlargement withearly seminiferous tubular maturation has also been reported 14. These abnormalitiespromptly subside with the correction of the hypothyroid state, and are explained byspillover of the action of TRH on gonadotropes and of TSH on FSH receptors 15,16.

Alterations in both androgens and estrogens associated with hypothyroidism arerather complex and are due to the consequences of thyroid hormone deprivationon the production, metabolic pathways, and serum transport of these steroids. Theconcentrations of both testosterone and estradiol in serum are decreased, predomi-nantly due to a diminution in the concentration of the carrier sex hormone-bindingglobulin (SHBG) 17, but because of the concomitant increase in the unbound fractionof the steroids, their absolute free concentration remains normal.

The metabolic clearance rate of testosterone increases in hypothyroidism 18,19. Theconversion ratio of testosterone to androstenedione increases and that to andros-

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terone decreases 18,20.

9.5.10 ENDOCRINE SYSTEMPituitary. Thyrotroph hyperplasia caused by primary hypothyroidism may result insellar enlargement, particularly when the condition has remained untreated for along period of time 1,2. Rarely, such hyperplasia may give rise to a pituitary macroade-noma that shrinks after thyroxine replacement 3,4. The serum prolactin concentrationis elevated in approximately one-third of patients with primary hypothyroidism 5.The hyperprolactinemia is modest in degree and is rarely associated with galactor-rhea 6 ,37 . When present, it subsides with thyroid hormone replacement in conjunctionwith the reduction in the serum prolactin level. Since thyroid hormone decreasesthe mRNA for pre-pro TRH in the paraventricular nuclei, it is conceivable that hy-pothyroidism leads to increased TRH secretion, unopposed by thyroid hormones,with consequent hyperprolactinemia. In contrast, the growth hormone response toinsulin-induced hypoglycemia is blunted in hypothyroidism 7. Growth hormone se-cretion is decreased in hypothyroidism related to an increase in hypothalamic so-matostatinergic tone 8, resulting in low serum IGF-1 concentrations 9. It may causegrowth retardation in hypothyroid children. Serum IGF-2, IGFBP-1 and IGFBP-3 alsofall, whereas IGFBP-2 rises; these changes are reversible upon treatment 10. A recentstudy reports slightly different results: IGF-1 and IGFBP-3 in hypothyroid patientsindeed were lower than in healthy volunteers but did not change upon replacementtherapy with levothyroxine, whereas the raised levels of IGFBP-1 in hypothyroidismdecreased significantly after therapy 36 .

Adrenal cortex. Adrenal steroid hormone production and metabolism are consider-ably affected. Serum cortisol levels are normal, but the turnover time is slowed. Thisslowing is principally due to a decrease in the rate of cortisol oxidation as a result ofreduced 11- -hydroxysteroid dehydrogenase activity 11. Conjugation with glucuronicacid in the liver is normal 12. Reflecting these alterations, urinary 17-hydroxycorticoid(as well as 17-ketosteroid) excretion is reduced 11,13. The turnover rate of aldosteroneis also decreased in hypothyroidism 11. This reduction is probably due to an alterationin steroid reductases that tends to diminish the proportion of androsterone formedand reciprocally increases the level of the etiocholanolone metabolite 14. The serumconcentration of aldosterone is low or normal 15. Renin activity is also often reduced,as is the sensitivity to angiotensin II 16.

Adrenal responsiveness to adrenocorticotrophic hormone (ACTH) may be reduced,or the response may be delayed until the second and third days of the standardACTH test, with an actual augmentation of the total response 17. The adrenal glandsoften atrophy. Pituitary responsiveness to the metyrapone test has been variable.Normal but delayed peak response 18, impaired response 19, or even lack of response19has been reported. Grossly impaired responses to the stimulation with lysine-8-vasopressin and a delayed increase in serum cortisol levels after insulin-induced hy-poglycemia have also been observed 20,21,22.

A general picture of adrenal function in the hypothyroid patient who is not understress seems clear. Adrenal steroid metabolism and production decrease. The de-creased production is accomplished automatically by the pituitary through decreasedACTH secretion. The result is a normal concentration of free cortisol in the serum.Presumably, sufficient hormone is produced for the reduced needs of the hypothy-roid subject. Whether steroid production can be augmented sufficiently in times ofstress is not clear, but the provocative test results suggest that these patients usuallyhave a mildly impaired hypothalamic-pituitary adrenal axis 23,24.

9.5.11 HEMATOPOIETIC SYSTEMErythrocytes. In hypothyroidism, plasma volume and RBC mass are both dimin-ished, and blood volume is decreased. Anemia of mild degree is commonly present,

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and the hemoglobin level may be as low as 8 to 9 g/dl. In two reports on a largeseries of patients with hypothyroidism from various causes, the incidence of anemiaranged from 32 percent 1 to as high as 84 percent 2. The anemia may be a result of aspecific depression of marrow that lacks thyroid hormone 3 or may be due to bloodloss from menorrhagia, to decreased absorption because of gastric achlorhydria, toconincident true Addisonian pernicious anemia, or to a decreased absorption of vi-tamin B12 which has been found to occur in certain patients with myxedema as aresult of diminished intrinsic factor or diminished production of erythropoietin bythe kidney. The erythropoietic effect of thyroid hormone is mediated through ery-thropoietin 4. This substance increases RBC production by stimulating the erythroiddifferentiation of the bone marrow, and its secretion by the kidney appears to be re-lated to the oxygen tension of the tissue. Anemia caused by hypothyroidism per semay be normocytic or macrocytic and respond to thyroid therapy. If iron deficiencydevelops from menorrhagia, a hypochromic and microcytic anemia may occur. Thiscondition usually responds to iron alone, but may respond optimally only to com-bined iron and thyroid hormone 5. Hypothyroidism per se causes diminished bloodcell formation probably as a response to decreased oxygen demand 6. Plasma andRBC iron turnover are decreased, and the bone marrow is frequently hypoplastic.The relationship between hypothyroidism and pernicious anemia has been well es-tablished. Patients have been reported who developed pernicious anemia while hy-pothyroid, and who lost their need for parenteral vitamin B12 when hypothyroidismwas treated. It is also known that some hypothyroid patients absorb oral vitamin B12poorly, and the defect is sometimes corrected by intrinsic factor 7,8. After thyroidtherapy, the absorption defect may disappear or may persist 8. The incidence of per-nicious anemia is higher than normal in myxedematous persons 5,8. In Tudhope andWilson’s series of 73 patients with spontaneous primary hypothyroidism, 12.3 per-cent had true Addison’s anemia that responded to vitamin B12 8. They believe thatmacrocytic anemia in hypothyroidism should not be accepted as a manifestation ofthyroid hormone lack per se, but that it is due instead to the increased coincidenceof Addison’s anemia. Half of the patients with Addisonian anemia have serum anti-bodies against the thyroid gland and half of the patients with Hashimoto’s thyroiditishave antibodies against gastric cell cytoplasm, parietal cells or intrinsic factor.

Megaloblastic anemia due to folic acid deficiency has also been demonstrated in hy-pothyroidism. Reduced intestinal absorption secondary to hypothyroidism may beresponsible for this deficiency, as suggested by the changes observed in a patientgiven tritiated pteroylglutamate before and after treatment with thyroid hormone9. Also, a peculiar RBC abnormality has been described in patients with untreatedhypothyroidism 10: a small number of irregularly contracted RBCs resembling burrcells are present. The significance of this condition, which may be reversed by theadministration of thyroid hormone, is unknown.

Leucocytes and thrombocytes. Granulocyte, lymphocyte and platelet counts are usu-ally normal in hypothyroidism. Leukopenia might indicate associated vitamin B12or folic acid deficiency. Mean platelet volume can be decreased. The erythrocyte sed-imentation rate may be elevated in uncomplicated hypothyroidism 11.

Hemostasis. Hypothyroid patients may have bleeding symptoms such as easy bruis-ing, menorrhagia, or prolonged bleeding after tooth extraction. The most frequent de-fects in hemostasis are prolonged bleeding time, decreased platelet adhesiveness, andlow plasma concentrations of factor VIII and Von Willebrand factor 12,13. Desmo-pressin rapidly reduces these abnormalities 14, and may be of value for the acutetreatment of bleeding or as cover for surgery. Usually the clinical relevance of theseabnormalities is limited, as illustrated by no excess blood loss or bleeding complica-tions during and after surgery in a large series of hypothyroid patients 15.

In patients with moderate hypothyroidism a hypofibrinolytic state has been found,which carries a risk of developing thrombosis 16. In contrast, patients with severehypothyroidism have low levels of von Willebrand factor and activation of the fibri-nolytic system; its clinical relevance is debatable 16.

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9.6 COURSE OF THE DISEASEAlthough technologically dated, one of the most charming and clear descriptions ofa typical case of myxedema is that given by William M. Ord 1in Allbutt’s System ofMedicine, published first in 1897. It is as follows:

THE PICTURE OF THE DISEASE"Thirty years ago the writer of this article had occasion to investigate the case of alady suffering from myxedema in a most definite form, and therefore offering com-plete opportunity of studying the symptoms and the relations of the disease. Thepatient, a lady of thirty-five, who had several children, presented an appearance sug-gestive of Bright’s disease, yet, although she was greatly swollen on the whole of herbody, on careful examination the swelling did not appear to be due to an ordinarydropsy. There was nowhere any pitting on pressure, and there was no albuminuriain the slightest amount. The diagnosis of chronic Bright’s disease without albumin-uria at first suggested itself, but on further examination many symptoms not knownto be related with Bright’s disease came under the eye. The face, very much swollenin all parts, was particularly swollen in the eyelids, upper and lower, in the lips, andin the alae nasi. There was a flush, very limited, over the malar bones, contrastingwith a complete pallor over the orbital regions. The eyebrows were greatly raised bythe effort to keep the lids apart. The skin of the face, and indeed of the whole body,was completely dry, rough and harsh to the touch; not exactly doughy, but giving asensation of the loss of all elasticity or resilience. The hair was scanty, had no propergloss, and was much broken. In the absence of all signs of visceral disease the condi-tion of the nervous system was such as to attract much attention. The physiognomywas singularly placid at most times, less frequently heavy, with signs of somnolence,very rarely alert. In interviews the patient was imperturbably garrulous to a degreethat could not fail to attract attention. For many minutes she would talk without ces-sation until obliged to stop and take a good breath. What she said was not altogetherrelevant, but it had to be said. All interrupting questions were disregarded. If, at theend of a small pause, she was asked to put her tongue, she ignored the request, butat the end of a varying time, when her breath became short, she would put out hertongue for a long time. She dealt in the same way with questions put to her in re-spect of the points raised by her statements. Her letters were frequent, voluminous,and, as regarded handwriting, very good. Her speech was slow and laboured. Therewas some difficulty in it, evidently due to the swelling of the lips, but was more thanthis: the words hung in a way that indicated nervous as well as physical difficulty,and inflexions of the voice were wanting. The tones of the voice were leathery, andsuggested rather those of an automaton. The proper timbre was quite lost. Doubtlessthis was in part, again, due to obvious thickenings in the fauces and the larynx; butit did not in any way resemble the character of voice observed in ordinary swellingsof those parts. Her temper was singularly equable, she was the most tender and so-licitous of mothers, and in a long course of years during which she was under thewriter’s observation no word of unkindness or suspicion fell from her lips. Lethargywas an impressive part of her mental condition. Memory was slow, but correct. Shethought slowly, performed all movements slowly, and was slow in receiving impres-sions. Her toilet, and she was no fashionable person, occupied hours. Her householdduties could never be overtaken, and she had to seek assistance. Her gait presented adistinct ataxic quality. As her bulky body moved across a room, there occurred at eachstep forward a quiver running from the legs upwards, such as may be seen in peopleunder the influence of great emotion, as in Lady Macbeth. This appeared to be due toa want of complete concert in the action of the flexors and extensors of the body, theflexors acting for the most part in advance. The interval between the action of the twosets of muscles was at some times extreme enough to determine falls, not in any wayproduced by obstacles. She fell forward on her knees, and, as a result, she sustainedfracture of the patella on one side, and the patellar tendon on the other. Similar con-ditions existing in the head and neck produced excessive distress. From time to timethe head would fall forward in spite of all voluntary effort to prevent it. The chin

30


would then rest on the upper part of the sternum, as is seen in cretins. Sometimesby prolonged exertion of the will, sometimes with the assistance of the hands, thehead would be raised, not always to good effect; for unless great care were exercisedthe head would fall backwards with a suddenness that was alarming. There was noobvious defect of the sense of touch, but it must be admitted that the speed of thereception of tactile sensations was not noted. After the establishment of the diseaseshe bore two children; on both occasions severe postpartum haemorrhage occurred.She had no other haemorrhages. The first impression was, as I said above, that thecase was one of Bright’s disease without albuminuria. The urine was examined reg-ularly for years without detection of albumin, and there were no such changes in theheart and arteries as belong to Bright’s disease. After ten years, however, albuminappeared in the urine, and the patient died ultimately with symptoms of contractinggranular kidney. A postmortem examination could not be obtained, and therefore thecondition of the thyroid gland and of the kidneys cannot be recorded."

ONSET OF THE DISEASEThe onset of naturally occurring hypothyroidism is insidious. The patient is oftenunaware of it, as may be friends and relations. As the gland is gradually replacedby fibrous tissue, lymphocytic infiltration, or both, the serum hormone levels andmetabolic rate begin slowly to fall. The first symptoms may be a decrease in sweatingand dislike of cold. They may be present alone for a period of years before dramaticevents occur. One of our patients gave a story of marked hypersensitivity to cold for12 years, at the end of which time the picture of full-blown myxedema developed.Sometimes the presenting symptom may be a demand for a warmer room or moreclothing. Sometimes a mere decrease in activity due to listlessness, lack of energy,or fatigue, is the first change noted. In other patients, mental dullness or drowsinessmay be observed. We have also seen the opposite change, namely, nervousness andirritability, or even peevishness in the exceptional case.

Progressive constipation or increase in menstrual flow may occasionally be the firstevent. So, too, may any of the following: deafness, falling hair, thick speech, dizziness,puffiness of the face, headache, pallor, weight gain, or fatigue. When hypothyroidismoccurs more suddenly, as after surgical thyroidectomy or RAI therapy, the symptomsmay not be so insidious, and indeed may be quite upsetting to the patient. Muscu-loskeletal symptoms such as frequent cramps may be distressing, and acute depres-sion or acute anxiety may appear. Thus, the clinical course may be much influencedby the cause of the hypothyroid state. Obvious symptoms and signs usually appearas the thyroxine (T4) level falls below normal. Of these symptoms, nonpitting edema,from which myxedema derives its name, is pathognomonic. It is a specific thyropri-val sign, and when it develops, the disease is in the full-blown state. There may belittle apparent change in the patient’s appearance or condition for several years. Dur-ing such a period the patient may be well off subjectively. The increased sensitivity tocold can be met by maintaining the living area at an unduly warm temperature. Thedecreased energy makes the person content to do little or nothing. The myxedema-tous state is characterized by an amazing placidity. The terminal stage may be calledmyxedematous cachexia.

MYXEDEMATOUS CACHEXIAMyxedematous cachexia is characterized by an intensification of all symptoms andsigns. There is great thickening of the tongue, thickness, dryness and coarseness ofthe skin, thickening and brittleness of the nails, falling and brittleness of the hair, pro-gressive decrease in activity and responsiveness, and a closer and closer approachto a purely vegetative existence. Although the mucous edema persists - and indeedtends to increase - body fat may disappear, so that actual wasting takes place. Af-ter this stage has persisted for an indefinite period of months or even years, deathtakes place because of intercurrent infection, congestive heart failure, or both. The

31


final symptom is coma, which may last for days. In the untreated patient, the lengthof time between the first symptoms and death may be as long as 15 years. It is, fortu-nately, seldom nowadays that one witnesses the natural termination of the disease. Itis seen only when the patient is already moribund when he or she comes to the physi-cian, the diagnosis previously having been overlooked or where severe myxedemais present in association with another serious illness. In the Report on Myxoedema,which was published before the discovery of the cure of the disease, the duration isgiven as 10 years or more. The evolution of the symptoms of myxedema is slowlyprogressive. If one compares patients with myxedema of 3, 6 or 12 years’ duration,although all may have classic symptoms and identical thyroid function test results,the clinical picture will be more intense at 6 years than at 3 and still more at 12. Themental manifestations, and the integumentary changes in particular, intensify as theyears pass. Such severe manifestations of hypothyroidism are rarely seen in the cur-rent era. Patients and their friends and relatives are often strangely unaware of evi-dence of myxedema. Often patients are identified during treatment for some entirelyunrelated disorder. Myxedema has been called a "consultant’s diagnosis", becausethe changes that appear as the disease develops are so subtle and gradual that theyare often overlooked by the patient’s family physician. This fact is becoming less truewith the ready availability of objective diagnostic tests.

9.7 DIAGNOSIS OF HYPOTHYROIDISMEvaluation of a patient suspected of hypothyroidism starts with obtaining conclusiveevidence that thyroid hormone deficiency is absent or present. Clinical examinationsuffices to provide a definitive answer in very severe cases of thyroid hormone defi-ciency, but is less accurate in mild cases. Biochemical proof of thyroid hormone defi-ciency is thus required in the vast majority of patients. If hypothyroidism is demon-strated, the next question to be answered is which disease entity has caused the hy-pothyroid state (nosological diagnosis). Delineation of the cause of hypothyroidismis relevant for identification of patients with potentially reversible hypothyroidism;it migh also give a clue for the existence of other conditions associated with a specificcause. The diagnostic process is schematically represented in Table 9-9.

Table 9. Schematic approach of the patient suspected of hypothyroidism.

Stage 1 Is hypothyroidism present?• A. Clinical assessment: compositeclinical score

• B. Biochemical assessment: TSHand FT4 assays

Stage 2 If hypothyroidism is present, what is thecause?

• A. Clinical assessment: history,goiter

• B. Biochemical assessment: TPOantibodies; sometimes thyroidalradioiodine uptake

9.7.1 CLINICAL EVALUATION (STAGE 1A)Table 9-10 lists the relative frequency of symptoms and signs accumulated by Ler-

32


man in a study of 77 myxedematous patients in one thyroid clinic and by Murray ina study of 100 patients with primary hypothyroidism, 15 pituitary patients, and 100normal control subjects. This analysis identifies the cardinal manifestations of the dis-ease. It also discloses that a certain number of manifestations are occasionally foundin overt myxedema that are somewhat more suggestive of hyperthyroidism than ofhypothyroidism. Under this heading may be listed dyspnea, nervousness, palpita-tions, precordial pain, loss of weight, and emotional instability. These symptoms arealso found in normal control subjects in nearly the same frequency.

Many symptoms typical of primary hypothyroidism are not commonly found in pi-tuitary hypothyroidism - for example, coarse skin, thick tongue, coarseness of hair,peripheral edema, hoarseness, and paresthesias.

Table 10. Incidence of symptoms and signs in hypothyroidism

Lermans’sSeries

Murray’s Series

Symptomsand Signs

Percent of 77Cases ofPrimaryHypothyroidism

Percent of100 Cases ofPrimaryHypothyroidism

Percent of 15Cases ofPituitaryHypothyroidism

Percent of100 NormalControlSubjects

Weakness 99 98 100 21

Dry skin 97 79 47 26

Coarse skin 97 70 7 10

Lethargy 91 85 80 17

Slow speech 91 56 67 7

Edema ofeyelids

90 86 40 28

Sensation ofcold

89 95 93 39

Decreasedsweating

89 68 80 17

Cold skin 83 80 60 33

Thick tongue 82 60 20 17

Edema of face 79 95 53 27

Coarseness ofhair

76 75 40 43

Cardiacenlargement(on x-ray film)

68 -- -- -- 14

Pallor of skin 67 50 87

Impairedmemory

66 65 67 31

Constipation 61 54 33 10

Gain in weight 59 76 47 36

Loss of hair 57 41 13 21

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Lermans’sSeries

Murray’s Series

Symptomsand Signs





Pallor of lips 57 50 -- --

Dyspea 55 72 73 52

Peripheraledema

55 57 0 2

Hoarseness 52 74 33 18

Anorexia 45 40 -- 15

Nervousness 35 51 53 42

Menorrhagiaa 32 33 -- --

Deafness 30 40 26 15

Palpitations 31 23 13 20

Poor heartsounds

30 -- -- --

Precordialpain

25 16 7 9

Poor vision 24 -- -- --

Fundus oculichanges

20 -- -- --

Dysmenorrhea 18 -- -- --

Los of Weight 13 9 26 23

Atrophictongue

12 -- -- --

Emotionalinstability

11 -- -- --

Chokingsensation

9 -- -- --

Fineness ofhair

9 -- -- --

Cyanosis 7 -- -- --

Dysphagia 3 -- -- --

Brittle nails -- 41 13 20

Depression -- 60 73 41

Muscleweakness

-- 61 73 21

Muscle pain -- 36 13 17

Joint pain -- 29 26 24

Paresthesia -- 56 13 15

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Lermans’sSeries

Murray’s Series

Symptomsand Signs





Heatintolerance

-- 2 0 12

Slowcerebration

-- 49 67 9

Slowmovements

-- 73 60 14

Exophthalmos -- 11 0 4

Sparseeyebrows

-- 81 80 58

aPremenopausal patients

The diagnosis of severe hypothyroidism is relatively straightforward on clinicalgrounds. All of the manifestations mentioned in the above discussion are present,and laboratory testing merely confirms the high index of clinical suspicion.However, severe hypothyroidism has become increasingly rare due to physicians’raised level of consciousness about the relatively high prevalence of this disease inwomen and the ease of making a laboratory diagnosis. Rather it is the more sublteor unusual presentations of hypothyroidism that may present difficulties 1. Sincelaboratory confirmation of hypothyroidism is straightforward, the critical factor insuccessful diagnosis is maintaining a high degree of suspicion. If the diagnosis is notsuspected in a patient with some of the typical manifestations of hypothyroidismat the first encounter, it may be several months before the physician reconsidersthis explanation for the patient’s complaints. Thus, hypothyroidism may be morereadily diagnosed by a consultant who has not seen the patient before, since boththe patient and the regular physician may have assumed that the many nonspecificsymptoms are insignificant or at least unrelated to a specific organic disease.

There are certain symptoms or signs that should, irrespective of other factors, leadto a biochemical evaluation for possible hypothyroidism. In the child or adolescent,growth retardation is one of these. The presence of an enlarged thyroid should triggera similar response. However, more subtle, less specific complaints, including depres-sion or other organic mental syndromes, muscle cramps, paresthesias, carpal tunnelsyndrome, hoarse voice, elevated cholesterol, pericardial effusion, arthritis, yellowskin (carotenemia), hyperkeratosis of the palms or soles, or menorraghia, can be man-ifestations of hypothyroidism. In addition, certain constellations of autoimmune dis-ease occur in concert with hypothyroidism, including primary adrenal insufficiency,type I diabetes, and pernicious anemia. The presence of any of these should lead tosearch for primary thyroid dysfunction.

Statistical methods have been applied to the clinical diagnosis of hypothyroidism,based on the frequency of symptoms and signs in patients and controls. Well-knownis the Billewicz score, composed of points given in a weighted manner for the pres-ence or absence of 17 symptoms and signs 2. Application of this score increases thepretest likelihood of hypothyroidism by 15-19% 3. A newly developed clinical scoreis, however, easier to perform and more sensitive 4(Table 9-11).

Table 11. Accuracy of 12 symptoms and signs in the diagnosis of primary hypothy-roidism 122.

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sensitivity(%)

specificity(%)

positivepredictivevalue (%)

negativepredictivevalue (%)

score ifpresent

Symptoms

impairmentof hearing

22 98 90 53 1

diminishedsweating

54 86 80 65 1

constipation48 85 76 62 1

paraesthesia52 83 75 63 1

hoarseness 34 88 73 57 1

weightincrease

54 78 71 63 1

dry skin 76 64 68 73 1

Physical signs

slowmovements

36 99 97 61 1

periorbitalpuffiness

60 96 94 71 1

delayedankle reflex

77 94 92 80 1

coarse skin 60 81 76 67 1

cold skin 50 80 71 62 1

Sum of all symptoms and signs present† 12§

† Add 1 point in women younger than 55 yr§ Hypothyroid, 6 points; intermediate, 3-5 points; euthyroid, 2 points.

The positive predictive value of this new score for hypothyroidism is 96.9% at a scoreof 6 points or more; the negative predictive value for the exclusion of hypothyroidismis 94.2% at a score of 2 points or less. 62% of all overt hypothyroid and 24% of subclin-ical hypothyroid patients are classified as clinically hypothyroid by the new score, asopposed to 42% and 6% respectively by the Billewicz score Figure 9-4.

36


Figure 4. Assessment of hypothyroidism by a clinical score, composed of 12 symp-toms and signs as listed in Table 3 (Reproduced with persmission(4)).

Age and smoking have been recognized as modifiers of the clinical expression of thy-roid hormone deficiency. Elderly patients have a smaller number of clinical signs thanyounger patients 5. Smokers have more severe manifestations of hypothyroidismthan nonsmokers 6.

9.7.2 LABORATORY EVALUATION (STAGE 1B)The assay of TSH in serum has proven to be the best single test for the exclusion ordetection of hypothyroidism. Using the flow-chart of Figure 9-2, the following resultscan be obtained:

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Figure 5. Flow-diagram for the biochemical diagnosis of hypothyroidism.

(Figure 9-5). Flow-diagram for the biochemical diagnosis of hypothyroidism.

1. TSH normal. Euthyroidism is almost certain, as primary hypothyroidism isexcluded. The only exception is the existence of central hypothyroidism. Asisolated TSH deficiency is very rare, clinical examination of the patient willusually provide sufficient clues (symptoms and signs of a pituitary mass, ofhypopituitarism, or of overproduction of pituitary hormones) to warrant fur-ther evaluation by a FT4 assay.

2. TSH elevated, FT4 decreases. This classical combination of test results indicatesprimary hypothyroidism. Test results are sometimes due to central hypothy-roidism or nonthyroidal illness when TSH is slightly elevated (5-15 mU/l).

3. TSH elevated, FT4 normal. Test results indicate most often subclinicalhypothyroidism, sometimes nonthyroidal illness.

4. TSH elevated, FT4 increased. A rarely encountered combination of test results,indicating either thyroid hormone resistance or TSH producing pituitary ade-noma.

5. TSH decreased, FT4 decreased. Central hypothyroidism accounts for these testresults, which, however, also can be observed in severe nonthyroidal illnessand after recently instituted treatment for thyrotoxicosis (131I, surgery, an-tithyroid drugs) or recent discontinuation of excessive thyroid hormone med-ication.

6. TSH decreased, FT4 increased or normal. Hypothyroidism is excluded. Resultsindicate overt thyrotoxicosis or subclinical hyperthyroidism respectively.

9.7.3 NOSOLOGICAL DIAGNOSIS (STAGE 2)The cause of the hypothyroid condition is in general easily established. Most informa-tive are a careful clinical examination and determination of TPO antibodies in serum.Particularly relevant questions in the history taking are: family history of thyroiddisease? recent delivery? previous thyroid surgery or 131I therapy? use of antithy-roid drugs? exposure to iodine excess? Symptoms and signs of a pituitary mass orof hypopituitarism suggest the presence of central hypothyroidism. Physical exam-ination may reveal a goiter (like the characteristic firm rubbery’ goiter in goitrous

38


Hashimoto’s hypothyroidism), but many if not most hypothyroid patients have nopalpable thyroid gland. High titers of TPO antibodies indicate chronic autoimmunethyroiditis, the most prevalent cause of hypothyroidism. Although most cases of hy-pothyroidism are permanent and require life-long treatment with thyroxine, a sub-stantial minority is transient in nature due to the natural course of the underlyingdisease entity. Elimination of the causal factor is possible only in a few patients inwhom the hypothyroid state is induced by antithyroid drugs or iodine excess. Table9-12 provides the physician with possible clues for assessing the likelihood of re-versible hypothyroidism in a particular patient. In selected cases further evaluationby thyroidal radioiodine uptake studies might be useful.

Table 12. Reversible causes of hypothyroidism

Etiology Frequency ofreversibility

Clues for potentialreversibility

chronic autoimmunethyroiditis

about 5% 7 goiter 8; preservedthyroidal radioiodineuptake 9; preserved T3response to TRH duringthyroxine treatment 10

postpartum thyroiditis up to 80% recent delivery; relativelylow titers of TPOantibodies

subacute thyroiditis almost 100% recent painful goiter

postoperative andpostradioiodinehypothyroidism

not unusual thyroidectomy or 131Itherapy in previous 6months

iodine-inducedmyxedema

high exposure to iodine excess;preserved thyroidalradioiodine uptake 11

drug-inducedhypothyroidism

high exposure to antithyroiddrugs or goitrogenicchemicals

9.8 TREATMENT OF HYPOTHYROIDISM

9.8.1 PHARMACOLOGY OF THYROID HORMONEREPLACEMENT PREPARATIONSLevothyroxine. L-thyroxine is prescribed as the sodium salt in order to enhance itsabsorption, which occurs along the entire small intestine 1,2. Intestinal absorption oforal T4 is on average 80% 3, and is greater in the fasting than in the fed state. Genericand brand-name levothyroxine preparations are mostly bioequivalent 4, but alteredbioavailability has been reported due to changes in the formulation of preparations5. Serum T4 concentrations peak 2 to 4 hours after an oral dose and remain abovenormal for approximately 6 hours in patients receiving daily replacement therapy 6,7.The gradual conversion of T4 into T3 in various tissues increases serum T3 concen-trations so slowly after thyroxine absorption that with daily levothyroxine adminis-tration, no significant changes in circulating free T3 are detectable. In North America,levothyroxine tablets are available in tablet strengths of 25, 50, 75, 88, 100, 112, 125,137, 150, 175, 200 and 300 µg. The long half-life of thyroxine of about 7 days allowstreatment with a singly daily tablet. Omission of an occasional tablet is of little rele-vance. Liothyronine. After oral administration of L-triiodothyronine sodium (which

39


is more readily absorbed than T4) peak levels of serum T3 are observed within 2 to 4hours 8. The serum T3 concentration may reach elevated values after a single dose of50 µg or even 25 µg, sometimes associated with cardiac symptoms like palpitations9. The half-life of T3 is approximately one day. Preparations of L-T3 are useful in themanagement of patients with thyroid cancer to shorten the period of hypothyroidismrequired for diagnosis and treatment of remaining tumor tissue with 131I. Desiccatedthyroid. Desiccated thyroid is prepared from porcine or bovine thyroid glands. In for-mer days desiccated thyroid was standardized by the organic iodine content, whichdid not distinguish between iodotyrosines and iodothyronines 10. Current guidelinesstipulate that one grain (65 mg) of desiccated thyroid contains about 44 µg T4 and 9µg of T3; the hormones are in the form of thyroglobulin 11,12. In our experience, the bi-ologic potency of a 1-grain desiccated thyroid tablet is about 75 to 88 µg T4. Becauseof the relatively high ratio of T3 to T4 in desiccated thyroid, patients receiving anamount of this medication adequate to normalize serum TSH generally have serumT4 concentrations in the lower half of the normal range. Serum T3 concentrations willvary in such patients, depending on the interval between ingestion of the medicationand the time of blood sampling. The time course of the absorption of T3 is similarwhether it is contained in thyroglobulin or free in the tablet, with peak levels approx-imately 2 to 4 hours after oral administration 8. Combinations of T3 and T4. Liotrix,the only combination preparation currently available in the United States, contains50 µg T4 and 12.5 µg T3/1 grain equivalent, but is biologically equivalent to a 65 mg(1 grain) tablet of desiccated thyroid. Recent studies in thyroidectomized rats havedemonstrated that restoration of the euthyroid state in all tissues can only be restoredby the combination of T4 and T3, and not by T4 alone 13. This finding has aroused newinterest in combinations of T3 and T4. In hypothyroid patients who were euthyroidunder stable thyroxine treatment, replacement of 50 µg T4 of the usual dose of T4 by12.5 µg T3 improved mood and neuropsychological functions in a cross-over studydesign, without suppressing serum TSH 14, 16. However, two subsequent randomizedclinical trials did not demonstrate any benefit of the T4+T3 combination therapy overtherapy with T4 alone 17,18 . One may argue that the disappointing results obtained sofar with combination therapy are caused by relatively high doses of T3 as comparedto the applied dose of T4, resulting in T4 to T3 ratio?s lower than the T4 to T3 ratio ofabout 10 which is the physiological ratio of T4 to T3 secretion by the thyroid gland.A future perspective might thus be combination preparations containing approxi-mately 100 µg of T4 and 10 µg of T3 with the triiodothyronine in slow-release formto avoid adverse cardiac effects 15. Such preparations are not yet available for clinicalvalidation studies. It remains to be established whether combination therapy withT4 and T3 in doses mimicking their thyroidal secretion rates might improve the im-paired psychological well-being which has been observed in a subset of hypothyroidpatients despite adequate doses of levothyroxine 19 .

9.8.2 REPLACEMENT WITH THYROXINEOf the available thyroid hormone replacement preparations, thyroxine is presentlyrecommended as the drug of choice in view of its long half-life ready quantitation inthe blood, ease of absorption, and the availability of multiple tablet strenghts 1-4. In-stitution of therapy. The rapidity with which normal thyroid hormone levels shouldbe restored depends on a number of factors, including the age of patient, the durationand severity of the hypothyroidism, and the presence or absence of other disorders,particularly those of the cardiovascular system. Most patients under the age of 60 canimmediately begin a complete replacement dose of 1.6 to 1.8 µg levothyroxine/kgideal body weight (about 0.7 to 0.8 µg/1b). Requirements for children and infantsare discussed separately and are higher than those for adults between the ages of20 and 70. The cause of hypothyroidism also influences replacement in that patientswith total thyroidectomy or severe primary hypothyroidism have slightly higher re-quirements than do patients who become hypothyroid after radioiodine or surgicaltreatment for Graves’ disease 5. The latter group may have some residual thyroidfunction that is autonomous, and thus a complete replacement dose is excessive. Formost women, a complete replacement dose will be between 100 and 150 µg per day

40


and, for most men, between 125 and 200 µg per day. Pretreatment serum TSH pre-dicts to a certain extent the daily maintenance dose of levothyroxine in patients withprimary hypothyroidism (Figure 9-6) 6.

Individual l-T(4) requirements are dependent on lean body mass. Age- and gender-related differences in l-T(4) needs reflect different proportions of lean mass over thetotal body weight. An estimate of lean mass may be helpful to shorten the time re-quired to attain a stable dose of l-T(4), particularly in subjects with high body massindex values that may be due either to increased muscular mass or to obesity. (J ClinEndocrinol Metab. 2005 Jan;90(1):124-7. Lean body mass is a major determinant oflevothyroxine dosage in the treatment of thyroid diseases. Santini F, Pinchera A, Mar-sili A, Ceccarini G, Castagna MG, Valeriano R, Giannetti M, Taddei D, Centoni R,Scartabelli G, Rago T, Mammoli C, Elisei R,Vitti P.)

Figure 6. Relationship between the optimal daily dose of levothyroxine sodiumand the mean pretreatment serum TSH concentration in patients with primary hy-pothyroidism. Simple linear regressions are shown for two subgroups calculatedaccording to the daily dose of L-T4 divided at the median dose of 125 µg; the in-tercept of these two correlation lines occurs at the TSH concentration of 36 mU/l.(Reproduced with permission)6.

Figure 9-1. Relationship between the optimal daily dose of levothyroxine sodium andthe mean pretreatment serum TSH concentration in patients with primary hypothy-roidism. Simple linear regressions are shown for two subgroups calculated accordingto the daily dose of L-T4 divided at the median dose of 125 µg; the intercept of thesetwo correlation lines occurs at the TSH concentration of 36 mU/l. (Reproduced withpermission) 6.

Full replacement doses should not be administered initially to patients over the ageof 60, to patients who have a history of coronary artery disease, or to patients withlong-standing severe hypothyroidism. While levothyroxine improves cardiac func-tion in patients with hypothyroidism and increases cardiac output and decreasessystemic vascular resistance and end-diastolic volume, it also increases myocardial

41


oxygen consumption. Thus, while patients with coronary artery disease and anginamay benefit from reversal of their hypothyroid state, to avoid precipitating acute my-ocardial ischemia, the dose should be titrated, starting with 25µg a day and increasedby increments of 25 µg at 8-week-intervals until serum TSH falls to normal or symp-toms of angina worsen or appear. A similar slow approach is prudent in patientswith long-standing, severe hypothyroidism, also because occasionally psychosis oragitation occurs during the initial phase of replacement in such cases 7,8,9.

In the patient given what is thought to be a complete replacement dose of levothy-roxine (SYNTHROID), a TSH and free T4 index should be measured about 2 monthsafter therapy begins to establish that the estimated dose is appropriate for the patient.At that time, serum TSH may be still elevated, indicating the need for a modest in-crease in dose, or TSH may be suppressed, indicating that a reduction is in order. Thisis usually done in 12- to 25-µg increments, depending on the patient 10. These studiesshould be repeated again in 2 months to titrate proper dosage. After proper dosagehas been achieved, the test should be repeated yet again after the patient has beeneuthyroid for approximately 6 months. This is because in certain patients, normal-ization of thyroxine clearance may require more than 8 weeks, and a dose of levothy-roxine that is adequate when the patient is metabolizing thyroxine more slowly maybe inadequate when the patient is euthyroid. This dose should be continued andmonitored on an annual basis. In patients with severe primary hypothyroidism, fewadjustments will be required after the initial titration until the eight decade. How-ever, patients with Graves’ disease who have had radioactive iodine may requiredosage adjustments up to as long as 5 to 10 years after treatment is begun. A sim-ilar course may be followed by patients who have had subtotal thyroidectomy forGraves’ disease due to the slow deterioration of residual thyroid function.

Therapy should be monitored with TSH measurements (using an immunometric as-say) and estimates of free T4. As the goal of levothyroxine therapy is to normalize thethyroid status of the patient, and as serum TSH provides the most sensitive and read-ily quantification of thyroid status in the patient with primary hypothyroidism, oneaims at TSH values in the low normal range. Serum FT4 concentrations will generallybe above the middle of the normal range or slightly elevated if serum TSH concen-trations are normalized, but serum T3 concentrations (predominantly derived fromT4-5’-monodeiodination) will be in the midnormal range 11. In patients with centralhypothyroidism one should rely primarily on serum FT4 and T3 12; the required re-placement dose will frequently suppress serum TSH values to below 0.1 mU/l 20

.

Clinical response. In general, serum thyroxine normalizes before serum TSH, andboth may normalize before the disappearance of all of the symptoms of hypothy-roidism. In the severely hypothyroid patient with long-standing disease, a numberof profound alterations may occur as the hypothyroid state is corrected. Thus, lossof weight, primarily due to mobilization of interstitial fluid as the glycosaminogly-cans are degraded, is prominent. The moon facies, coarse nasal voice, puffy fingers,deafness, and sleep apnea will all diminish. Many of nonspecific symptoms, such asfatigue or cold intolerance, will eventually reverse as well. Hair and skin abnormal-ities take longer to improve. Despite weight loss due to fluid loss, the obese patientshould not expect more than a 10-pound weight change, particularly if serum TSHvalues are only modestly elevated. Virtually all of the weight loss in hypothyroidismis associated with mobilization of fluid, and significant decreases in body fat rarelyoccur. While metabolic rate increases, in general, appetite increases as well, and anew equilibrium is established.

Treatment failures. There are few compliant patients whose symptoms and signs donot resolve after thyroid hormone administration. Patients with thyroid hormoneresistance sometimes present in this fashion. In patients whose symptoms do notimprove with levothyroxine therapy, one should establish that they are taking andabsorbing the medication and that it is effective in reducing TSH. The most com-mon cause of treatment failure is poor compliance with ingestion of thyroxine tablets.Compliance might be enhanced by the (supervised) administration of thyroxine onceweekly 13. A slightly larger dose than 7 times the normal daily dose may be required;

42


a singly weekly gift of 1000 µg T4 orally seems to be effective and well tolerated.

Potential adverse effects of treatment. Life-long treatment with thyroxine when prop-erly monitored, seems to be free of complications. Long-term morbidity and mortal-ity are normal 1-4. Thyroxine treatment in TSH-suppressive doses, however, mightgive reason for some concern as it has been associated with detrimental effects on theheart and the bones. A TSH value of =0.1 mU/l has been identified as a risk factorfor the development of atrial fibrillation 14. Long-term levothyroxine therapy in TSH-suppressive doses may cause left ventricular hypertrophy 15, and increases the risk ofischemic heart disease in patients under the age of 65 years 16. TSH-suppressive dosesof levothyroxine have been associated with bone loss in some but not all studies. Arecent extensive meta-analysis concluded that indeed bone mineral density was re-duced in hypothyroid patients with a suppressed TSH due to excessive levothyrox-ine therapy, but only in postmenopausal women 17. No or a minimal excess of bonefractures, however, has been observed in patients on levothyroxine even if TSH issuppressed 18,19,21,22.

9.8.3 SITUATIONS REQUIRING DOSE ADJUSTMENTTable 9-13 lists a number of circumstances in which dosage requirements of levothy-roxine may change in compliant patients. Patients who develop clinical malabsorp-tive disorders like gluten-induced enteropathy may require a change in dosage 1 ,26 .Malabsorption may also occur in patients who ingest large quantities of bran 2; thetiming of the dose should be adjusted to take this into account. Levothyroxine shouldbe administered several hours after the patient takes any of the agents listed thatcan block its absorption 27 , but the dosage or preparation used may still have tobe increased during therapy with some of these agents 3-7,28. There is an increase inthyroxine requirement in pregnant patients with primary hypothyroidism, probablyrelated to increased lean body mass and increased serum TBG 8,9. Patients with hy-pothyroidism planning to become pregnant should be instructed to report to theirphysician when pregnancy is confirmed, and the serum TSH and/or free T4 estimateshould be monitored and the levothyroxine dose adjusted upward as indicated. Themean increment in the required daily thyroxine dose is 50 µg; it may not occur untilas late as the sixth month but is often apparent by the second month of gestation.In a review of four series comprising a total of 108 women, serum TSH increased in58% and the mean L-T4 dose increased from 117 µg to 150 µg 24. Timely adjustmentof the thyroxine dose in early gestation might be relevant for infant development.Children of healthy women with FT4 levels below the 10th percentile (<10.4 pmol/l)at 12 weeks gestation have lower scores on a psychomotor developmental scale at 10months of age, compared to children of mothers with higher FT4 values (mean differ-ence 7.4, 95% CI 1.1 to 13.9) 10; psychomotor development was not related to materialFT4 at 32 weeks gestation. Children at the age of 7-9 years have a lower intelligencequotient if their mother was hypothyroid during pregnancy 11.The lowest IQ?s wereobserved in children whose mother was not treated for hypothyroidism during preg-nancy: 19% of such children had an IQ of #85, in contrast to 5% of the children whosemothers had a normal thyroid function during pregnancy. The data raise the issue ofscreening pregnant women for thyroid function disorders in the first trimester. Thedosage may by reinstituted at its pregestational level immediately after delivery. Es-trogen therapy may increase the need for levothyroxine and it is recommended tomeasure serum TSH approximately 12 weeks after estrogen therapy is initiated 25.

Several drugs (e.g. carbamezepine) induce enzymes of the cytochrome P450 class,which can accelerate thyroxine clearance via pathways that do not lead to T3 pro-duction 12-15. Under these circumstances, dosage must be increased to compensatefor this. Lastly, amiodarone and, theoretically at least, selenium deficiency may alsoblock T4 to T3 conversion 16,17. Androgen therapy in women with breast cancer hasalso recently been shown to reduce levothyroxine requirements by 25 to 50 percent20. The mechanism is not known, but thyroxine-binding globulin (TBG) levels aresignificantly reduced. In patients over the age of 70, levothyroxine requirements arereduced about 25 percent, related to the decrease of lean body mass with age 21,22,23.

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Hypothyroid patients with end-stage renal insufficiency need lower doses of T4 afterrenal transplantation 29 .

Table 13. Conditions requiring adjustment of the replacement dose of thyroxinefor hypothyroidism.

Increased dose requirement1. decreased intestinal absorption of T4

a. malabsorption (e.g. celiac disease) and short bowel syndrome 1

b. dietary fiber supplements 2

c. drugs: bile-acid sequestering agents (colestipol 3,cholestyramine 4), sucralfate 5, aluminium hydroxide 6, ferrous sulfate7

2. increased need for T4

a. weight gain

b. pregnancy 8,9

3. increased clearance of T4

a. phenobarbital 10, phenytoin 11, carbamazepine 12, rifampicin 13

4. precise mechanism unknown

a. amiodarone 14, sertraline 16, chloroquine 17

Decreased dose requirement1. decreased need for T4

a. weight loss

b. androgens 18

2. decreased clearance of T4

a. old age 19,20,21

9.8.4 INTERFERENCE WITH CO-EXISTENT CONDITIONSHypocortisolemia. The co-existence of thyroid hormone deficiency and glucocorti-coid deficiency is not rare. Primary hypothyroidism due to chronic autoimmune thy-roiditis is associated with primary adrenocortical insufficiency due to autoimmuneadrenalitis. The very cause of central hypothyroidism in many instances will alsoresult in ACTH deficiency and secondary adrenocortical insufficiency. If the two en-tities co-exist, it is important to replace glucocorticoid before starting thyroxine. For,treatment of hypothyroidism in patients with glucocorticoid deficiency may precipi-tate an adrenal crises because the adrenal is incapable to meet the increasing demandfor cortisol induced by the rise of the metabolic rate 10.

Ischemic heart disease. Although treatment of hypothyroidism with levothyroxinewill improve myocardial function and reduce peripheral vascular resistance, it will

44


increase the need for oxygen in the myocardium 1,2,3. In patients with an already com-promised myocardial blood supply due to coronary atherosclerosis, thyroxine treat-ment may provoke anginal symptoms. In a large series of hypothyroid patients, new-onset angina occurred in 2% upon thyroxine treatment; pre-existent angina worsenedin 16%, did not change in 46%, and improved in 38% 4. Patients with preexistingangina should be evaluated for obstructive coronary lesions before thyroxine therapybegins. Retrospective studies suggest that the possibility of myocardial infarction isgreater than is the possibility of an adverse event during angiography or angioplasty5-8. However, it is quite surprising that major surgery, such as coronary artery bypassgrafting, can be very easily withstood by the patient with even moderate hypothy-roidism as long as attention is paid to reducing the level of analgesics, maintainingadequate ventilation, and controlling the administration of free water 7. In a few pa-tients, remediable lesions will not be present or, even with bypass grafting, completecorrection of the hypothyroid state will not be possible. In such patients, submaxi-mal amounts of levothyroxine supplemented by other agents to enhance myocardialfunction may be helpful in allowing the reestablishment of normal thyroid function9.

Drugs. The metabolism of many drugs is slowed in hypothyroidism, resulting inhigher sensitivity to a loading dose and a lower maintenance dose. Marked respi-ratory depression can occur after a single small dose of morphine. An increase inthe dose of digoxin or insulin is sometimes noticed once euthyroidism has been re-stored. Treatment of adult growth hormone deficiency with rhGH decreases serumFT4 sometimes into the hypothyroid range, thereby unmasking the existence of cen-tral hypothyroidism or necessitating a higher dose of already instituted levothyrox-ine medication 11 .

9.9 MYXEDEMA COMADefinition and pathogenesis. Myxedema coma is a rare, life-threatening clinicalcondition in patients with long-standing severe untreated hypothyroidism in whomadaptive mechanisms fail to maintain homeostasis. Most patients, however, are notcomatose, and the entity rather represents a form of decompensated hypothyroidism1 ,2,10 . Usually a precipitating event disrupts homeostasis which is maintained inhypothyroid patients by a number of neurovascular adaptations. These adaptationsinclude chronic peripheral vasoconstriction, diastolic hypertension and diminishedblood volume; in this way a normal body core temperature is preserved. In severelyhypothyroid patients homeostasis might no longer be maintained if blood volumeis reduced any further (e.g. by gastrointestinal bleeding orthe use of diuretics),if respiration already compromised by a reduced ventilatory drive is furtherhampered by intercurrent pulmonary infection, or if CNS regulatory mechanismsare imparied by stroke, the use of sedatives or hyponatremia 2.

Diagnosis. The three key features of myxedema coma are 1:

1. Altered mental status. The patient may be entirely obtruded or may be rousedby stimuli. Usually lethargy and sleepiness have been present for manymonths. Sleep may have occupied 20 hours or more of the day and may haveinterfered even with eating. There may actually have been transient episodesof coma at home before a more complete variety developed.

2. Defective thermoregulation: hypothermia, or the absence of fever despiteinfectious disease. Usually coma comes on during the winter months. Theseverely myxedematous patient becomes essentially poikilothermic. Withcold weather the body temperature may drop sharply. The temperature issubnormal, often much depressed: a temperature of 74 F (23.3 C) has beenrecorded. A thermometer reading lower than the usual 97 F must be used, orhypothermia may be missed.

45


3. Precipitating event: cold exposure, infection, drugs (diuretics, tranquillizers,sedatives, analgetics), trauma, stroke, heart failure, gastrointestinal bleeding.The pulse is slow, and the absence of mild diastolic hypertension is a warningsign of impending myxedema coma 1. Diagnosis on clinical grounds is rela-tively easy once the possibility is considered. Any patient with hypothermiaand obtundation should be considered as having potential myxedema coma,especially if chronic renal insufficiency and hypoglycemia can be ruled out.The diagnosis can be confirmed by finding a reduced free T4 estimate andmarked elevation of serum TSH. Creatine phosphokinase is often elevated.Both hypoxia and hypercapnia may be present.

Treatment. Myxedema coma is a medical emergency. Early diagnosis, rapid admin-istration of thyroid hormones an adequate supportive measures (Table 9-14) are es-sential for the prognosis. The mortality with the current treatment regimen remains,nevertheless, high in the order of 20 percent 3.

Table 14. Recommendations for the treatment of myxedema coma.

hypothyroidism large initial intravenous dose of 300-500µg T4; if no response within 48 hours,add T3

hypocortisolemia intravenous hydrocortisone 200-400 mgdaily

hypoventilation don’t delay intubation and mechanicalventilation too long

hypothermia blankets, no active rewarming

hyponatremia mild fluid restriction

hypotension cautious volume expansion withcrystalloid or whole blood

hypoglycemia glucose administration

precipitating event identification and elimination byspecific treatment (liberal use ofantibiotics)

In view of the rarity of myxedema coma, it has been difficult to perform randomizedstudies to resolve the issue of whether T4 or T3 is the most appropriate treatment. Themortality rate, with the current treatment regimen, is estimated to be approximately20 percent 3 ,11 . There are advocates of T4 therapy alone 4, T3 therapy alone 5,6, andcombinations thereof 7. If T4 alone is used, it should be given parenterally in doses of300 to 500 µg to replace the calculated T4 deficit 8. Since the average volume of distri-bution of T4 in a 70-kg human is approximately 7 L, 420 µg should cause an increaseof 77 nM/L in the serum T4 concentration. Following this, 75 µg/day are given in-travenously. Advocates of T3 therapy point to the impairment of T4 to T3 conversioncharacteristic of hypothyroidism that is due to a combination of the low levels of typeI deiodinase as well as the generalized illness and inadequate caloric intake. Replace-ment should be given at a dose of 25 µg intravenously every 12 hours. The patient canbe switched to oral therapy when the circulatory system is stabilized and the patientis receiving other oral medications. Other authorities recommend a combination ofT4 and T3 giving 200 to 300 µg of T4 and 25 µg T3 intravenously as an initial dose7. The T3 is repeated 12 hours later and 100 µg of T4 24 hours later. This is followedby 50 µg T4 daily from the third day until the patient regains consciousness. Whiledeath associated with T3 treatment in higher doses has been reported 7, it is difficultto know whether this reflects a direct effect of this form of treatment or individualfactors in the patients’ illnesses. In addition to replacement of T4, intravenous gluco-corticoid should also be administred during the first days of therapy, since in severehypothyroidism pituitary-adrenal function is impaired, and the cortisol production

46


rate is lower. While this low production is adequate when cortisol metabolism is re-duced, as it is in hypothyroidism, the rapid restoration of a normal metabolic ratefrom the above treatment may precipitate transient adrenal insufficiency.

In addition, the patient should be intubated and measures taken to retain body heat.Central warming may be attempted but peripheral warming should not, since it maylead to vasodilatation and shock. The cutaneous blood flow is markedly reduced inthe hypothyroid patient in order to conserve body heat. Warming blankets will de-feat this mechanism. Mechanical ventilation may be needed, particularly when obe-sity and myxedema are combined. The thoracic and abdominal adipose tissue putsan added burden on the respiratory musculature and may lead to hypoxia, cardiacarrhythmia, and death. Hyponatremia is characteristic and free water restriction andthe use of isotonic sodium chloride will usually restore normal serum sodium, aswill improved cardiovascular function, which is one cause of the impaired free waterclearance. Serum glucose should be monitored. Supplemental glucose may be neces-sary, especially if adrenal insufficiency is present. Hypotension may develop, partic-ularly if myxedema is severe. Volume expansion is usually required to remedy this,since patients are usually maximally vasoconstricted. Dopamine should be added iffluid therapy does not restore efficient circulation.

Concomitantly, a vigorous search for precipitating factors should be instituted. De-termining whether an infection is present should be a priority, since as many as 35percent of patients with myxedema coma have infection. Since hypothyroid patientscannot mount an adequate temperature response, the usual signs of infection, includ-ing tachycardia, fever, and elevated white blood count, may be absent.

Prophylactic antibiotics are indicated until infection can be ruled out; upper respi-ratory infection should be eliminated. While the hypothyroid patient withstands thestress of surgery in general very well 9, inadvertently excessive narcotics, sedatives,and hypnotics can tip a severely hypothyroid patient into coma. Most patients beginto show increases in body temperature within the first 24 hours of treatment. Theabsence of an increase in body temperature within 48 hours should lead to consid-eration of more aggressive therapy, specifically T3 therapy if it has not already beeninitiated. Most patients regain consciousness within a few days.

9.10 SUBCLINICAL HYPOTHYROIDISMSubclinical hypothyroidism is defined as an increased serum TSH in the presenceof a normal serum FT4 concentration. Increased and normal refer to values aboveor within population-based reference ranges of these hormones. It is assumed thatthe increased TSH concentration is not caused by analytical interference in the TSHassay (e.g. by heterophilic TSH antibodies) or by non-thyroidal illness. If a slightly in-creased serum TSH is found, a second blood sample taken from the same individualmay occasionally contain a normal TSH concentration; this can be due to inter-assayvariation in the TSH assay (which is about 5-10%) or to ultradian and circadian TSHrhythms (but the relative risk of misjudging mean TSH serum levels by a single TSHdetermination between 07.00 and 17.00 hours is only 0.09% for values above 4.0 mU/l1).

Subclinical hypothyroidism may have endogenous causes (chronic autoimmunethyroiditis, subacute thyroiditis, postpartum thyroiditis) or exogenous causes(thyroidectomy, 131I therapy, antithyroid drugs, inadequate thyroid hormonereplacement therapy). Prevalence and natural history. The prevalence of subclinicalhypothyroidism is rather high. In the classical population-based study amongadults in the English county of Whickham the prevalence was 75 per 1000 womenand 28 per 1000 men 2; similar figures have been obtained in other studies (see §9.2).The higher prevalence of subclinical hypothyroidism in females than in males andin older than in younger subjects is in agreement with the higher prevalence ofthyroglobulin and thyroid peroxidase (microsomal) antibodies in women and inelderly people. The natural history of subclinical hypothyroidism is reasonably well

47


known. Spontaneous return of increased TSH values into the normal range occurs in5.5% after 1 year 3.

Progression to overt hypothyroidism ranges from 7.8% to 17.8% in various studies3,4,5. Another report indicates that approximately 30% of patients with subclinical hy-pothyroidism had developed overt hypothyroidism after 10 years; the higher the ini-tial TSH, the greater the risk 6. The 10-year probability to develop overt hypothy-roidism at an initial TSH value of 12 mU/l was ~27% in antibody-negative patientsbut ~57% in antibody-positive patients. The importance of thyroid antibodies is alsoevident from a Dutch study 7: 39.6% of 55-year old women with thyroid microso-mal antibodies had raised TSH levels 10 years later, in contrast to 3.2% of womenwithout antibodies 7. derived A Swiss follow-up study among subclinically hypothy-roid women reports a 10-year risk for progression to overt hypothyroidism of 0% inwomen with baseline serum TSH >4-6 mU/l, of 43% (3 percent per year) at base-line TSH levels of >6-12 mU/l, and of 77% (11 percent per year) at baseline TSH >12mU/l; the cumulative incidence of overt hypothyroidism was 23% among womenwithout TPO-antibodies and 58% among women with TPO-antibodies 56 . The mostextensive data are from a 20-year follow-up in the participants of the Whickham sur-vey 8: the incidence of overt hypothyroidism was 4.1 per 1000 women per year and0.6 per 1000 men per year. Risk factors were the initial presence of either a raisedTSH or thyroid antibodies (see also § 9.2). The annual incidence of hypothyroidismin women was 5% 8,9. Systemic manifestations. A number of abnormalities listed inTable 9-15, has been reported in some but not all subjects with hypothyroidism. Thedescribed abnormalities are in general minor, and more frequent in subjects with thehighest TSH values 10. Hypothyroid symptoms (especially dry skin, cold intoleranceand easy fatigability) occur more often than in controls 10,11, as also evident from aclinical symptom score for hypothyroidism 12(see § 9.7.1). An association with de-pression is reported. A study among healthy females with a family history of thyroiddisease, recruited by advertisement, indicated a higher lifetime frequency of depres-sion in subjects with subclinical hypothyroidism (56%) than in euthyroid subjects(20%) 14. Patients with major depression also have a poorer response to antidepres-sive drugs if they are subclinically hypothyroid 15.

Table 15. Abnormalities reported in some but not all subjects with subclinical hy-pothyroidism.

Symptoms• hypothyroid somatic complaints10,11,12

• impaired cognitive functions 13

• depression, mood disturbances 14,15

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Signs• low resting energy expenditure 16

• prolonged Achilles tendon reflextime 10,17

• impaired muscle energymetabolism 18

• decreased myocardial contractility11,20,21,22

• prolonged systolic time intervals11,19,20

• impaired nerve conduction latencyand amplitude 34

• impaired stapedial reflex 35

Biochemistry• high serum LDL cholesterol 30,31

• low serum HDL cholesterol 30,31

• high serum procollagen II peptide20

• high serum myoglobulin 10

• high serum creatine kinase 10,33

A slight increase in serum TSH is associated with a fall in resting energy expenditure16and lengthening of the Achilles tendon reflex time 10,17. Muscle energy metabolismis impaired: during exercise, blood lactate is significantly higher in subjects with sub-clinical hypothyroidism than in controls (18). Systolic time intervals like the Qkd time(the interval from the Q wave of the electrocardiogram to the pulse wave arrival timeat the brachial artery) and the PEP/LVET ratio (pre-ejection period divided by the leftventricular ejection time) were not different from controls in one study (19), but thePEP/LVET ratio decreased upon thyroxine replacement in two placebo-controlledclinical trials (although only in subjects with the highest pre-treatment PEP/LVETratio’s in one of these studies) 11,20. Left ventricular ejection function at rest or withmoderate exercise does not change upon thyroxine therapy in subclinical hypothy-roidism; it is improved by T4 treatment only at maximal exercise 21,22. The biologic sig-nificance of these subtle changes in myocardial contractility appears to be very small.Studies in the early seventies suggested preclinical hypothyroidism as a risk factorfor coronary heart disease, presumably via increased cholesterol levels 23,24. Much in-terest was thus aroused to evaluate whether or not subclinical hypothyroidism is as-sociated with hypercholesterolemia. The bulk of the evidence indicates that serum to-tal cholesterol, LDL-cholesterol and HDL-cholesterol in subclinical hypothyroidismare not different from those in age- and sex-matched controls 10,25-29; only a few stud-ies report higher LDL- and lower HDL-cholesterol values 30,31. The 20-year follow-upstudy in participants of the Whickham Survey, however, lend no support to the viewthat thyroid antibodies or subclinical hypothyroidism are risk factors for the devel-opment of ischemic heart disease 32. In contrast, a population-based cross-sectionalstudy of elderly women (mean age 69±7.5 years) living in The Netherlands, reportsthat subclinical hypothyroidism is associated with a greater age-adjusted prevalence

49


of aortic atherosclerosis (odds ratio 1.7, 95% CI 1.1 to 2.6) and myocardial infarc-tion (odds ratio 2.3, 95% CI 1.3 to 4.0) 41. Additional adjustment for body mass in-dex, serum cholesterol, blood pressure, smoking and the use of $-blockers did notaffect these estimates. The odds ratio?s were slightly higher in women with subclini-cal hypothyroidism and antibodies to thyroid peroxidase, but thyroid autoimmunityitself was not related to cardiovascular disease. The population attributable risk forsubclinical hypothyroidism associated with myocardial infarction was 14%, withinthe range of that for known major risk factors for cardiovascular disease (hyperc-holesterolemia 18%, smoking 15%, hypertension 14%, diabetes 14%). In this respectit is noteworthy that the increased cardiovascular risk associated with subclinical hy-pothyroidism seems to extend itself into the normal range of thyroid function 42. For,in euthyroid healthy volunteers the association of TSH with LDL cholesterol is mod-ified by insulin sensitivity, being absent in insulin-sensitive and strongly positive ininsulin-resistant subjects 42.

Treatment. Several double-blind placebo-controlled studies have been performed onthe usefulness of thyroxine replacement in subclinical hypothyroidism; some reporta greater benefit of thyroxine than of placebo, but others do not find any improve-ment of symptoms by T4 treatment. Hypothyroid symptoms improved in 47% ofT4-treated subjects and in 19% of placebo-treated subjects 11. During T4 treatment24% of the subjects improved as judged by psychometric test and their own rat-ing 20. A small improvement in a composite memory score was observed in activelytreated versus placebo-treated subjects 36. In another study of patients with subclin-ical hypothyroidism free from neuropsychological complaints, thyroxine treatmentimproved memory skils and decreased somatic complaints and obsessionality rating13. Two clinical scores assessing symptoms and signs of hypothyroidism (Billewiczand Zulewski scores) improved significantly in T4-treated but not in placebo-treatedpatients 51 . In contrast, still another study did not find significant differences in thechanges from baseline to 6 months between women in the thyroxine group and theplacebo group for body mass index, resting energy expenditure, LDL-cholesterol,or general health questionnaires 52 .With respect to serum lipids, a meta-analysisconcludes that normalization of serum TSH in subclinical hypothyroidism decreasesserum cholesterol on average by 0.4 mmol/l (95% CI 0.2-0.6 mmol/l) 37. A more re-cent meta-analysis also concludes that normalization of serum TSH decreases serumLDL-cholesterol by 0.26 mmol/l (95% CI 0.12-0.41 mmol/l) 43 . The reduction inserum total and LDL cholesterol may be larger in individuals with higher pretreat-ment cholesterol levels 43,51. The observed decrease in LDL-cholesterol is estimated todecrease the risk of cardiovascular mortality by 9-31% 51 . Lipoprotein (a) levels donot change upon normalization of TSH 53 . Levothyroxine treatment of subclinical hy-pothyroidism results in 6% reduction in supine mean arterial pressure, 14% increasein upright cardiac output, and 13%-20% decrease in systemic vascular resistance 54

.In a study among women with subclinical to mild hypothyroidism, progression ofarterial disease after 1 year had occurred in 20% of the T4-treated patients and in 60%of the untreated patients 38. The impaired left ventricular function at rest and systolicdysfunction on effort are reversed by restoration of euthyroidism 44 , as also evidentfrom a double-blind placebo-controlled study 55 .

Taken together, the findings (especially the high rate of progression towards overt hy-pothyroidism) argue against a "wait-and-see" policy and favor early thyroxine treat-ment 39. Improvement of hypothyroid symptoms, mood and cognitive functions maybe expected in 25-30% of patients. When in doubt because of nonspecific complaints,a trial of thyroxine treatment for 3-6 months can be considered. However, whetheror not subclinical hypothyroidism should be treated is still hotly delated; there arestrong defenders as well as strong opponents to levothyroxine treatment 45-48 . Arecent scientific review by a panel of experts concluded that data supporting asso-ciations of subclinical thyroid disease with symptoms or adverse clinical outcomesor benefits of treatment are few, and that the consequences of subclinical thyroid dis-ease are minimal 49 ; consequently, the panel recommended against routine treatmentof subclinical hypothyroidism, albeit recognizing the possible need for treatment inselected individual cases. Given the current state of affairs with a lack of controlledtrials reporting on long-term outcome, an algorithm as proposed by Cooper 50 might

50


be useful. A slightly modified algorithm is outlined in figure 9, providing guidelineson the appropriate management of the individual patient. The topic of subclinicalhypothyroidism has been extensively reviewed 40. A summary of key data is listed inTable 9-16.

Table 16. Summary of data on subclinical hypothyroidism.

Prevalence approximately 6% in generalpopulation

• > (factor 3)

• elderly > young

Natural history• normalization in appr. 5%

• progression to overthypothyroidism in appr. 5% per year,high risk in women with thyroidantibodies

Treatment • 25-30% improve on thyroxine

9.11 SCREENING FOR HYPOTHYROIDISMIn view of the rather high prevalence of thyroid function disorders and the avail-ability of a suitable screening test in the form of the sensitive TSH assay, the ques-tion arises if screening programs are warranted in the general adult population 1.Case-finding strategies have been employed successfully: previously unknown hy-pothyroidism was found in 0.64% of middle-age women in connection with screen-ing for cervical carcinoma 2, and in 0.3% of women attending a primary care unit3; the prevalence of subclinical hypothyroidism in the latter study was 1.2%.Case-finding in women over 40 years of age can be useful. Patients admitted to geriatricunits also benefit from routine testing as 2% to 5% have treatable thyroid disease, butpatients hospitalized with acute illness do not benefit from routine thyroid functiontests due to frequent interference of test results by the sick euthyroid syndrome 4.The cost-effectiveness of periodic screening for mild thyroid failure has been investi-gated using a state-transition computer decision model that account for case-finding,medical consequences of mild thyroid failure, and costs of care during 40 years ofsimulated follow-up 5. The cost-effectiveness of screening 35-year old patients with aserum TSH assay every 5 years was $ 9223 per QALY (quality-adjusted life year) forwomen and $22595 for men. The cost-effectiveness compares favorably with othergenerally accepted prevention programs. The authors recommend screening in thegeneral community for mild hypothyroidism with serum TSH (combined with serumcholesterol) every five years at the age of 35 years 5,6. A recent update on screeningfor thyroid disease in the general adult population, however, argues that the evi-dence of the efficacy of treatment for subclinical thyroid dysfunction is inconclusiveand that large randomized trials are needed to determine the likelihood that treat-ment will improve the quality of life in otherwise healthy subjects who have mildlyelevated TSH levels 7. On the other hand, the update favors office-based screening todetect overt thyroid dysfunction in women older than 50 years of age: in this group,1 in 71 women screened would benefit from relief of symptoms. Taken together, thepresently available data do not justify yet screening of the healthy adult populationfor hypothyroidism. Case-finding, i.e. testing on patients visiting their physician for

51


unrelated reasons, seems currently the best approach to detect previously unsus-pected hypothyroidism; it is especially worthwhile in women over 40 years of age.Table 9-17 provides a useful list of indications for screening’ for hypothyroidism 8.

Table 17. Indications for screening for hypothyroidism. (Reproduced with permis-sion) 8

EstablishedCongenital hypothyroidism

Treatment of hyperthyroidism

Neck irradiation

Pituitary surgery or irradiation

Patients taking amiodarone or lithium

Probably worth while

Type I diabetes antepartum*

Previous episode of postpartum thy-roiditis

Unexplained infertility

Women over 40 with non-specific com-plaints

Refractory depression; bipolar affectivedisorder with rapid cycling 10

Turner’s syndrome; Down’s syndrome

Autoimmune Addison’s disease

UncertainBreast cancer 11

Dementia

Patients with a family history of autoim-mune thyroid disease.

Pregnancy, looking for postpartum thy-roiditis*

Obesity

Idiopathic oedema

Not indicated

Acutely ill patients with no clinical rea-son to suspect thyroid disease

*Check thyroid antibodies; screen posi-tive patients post partum using thyroidstimulating hormone

ReferencesREFERENCES-Section 9.1

9.1.1. Gull WW: On a cretinoid state supervening in adult life in women. Trans ClinSoc London 1874; 7: 180.

9.1.2. Ord WM: On myxedema, a term proposed to be applied to an essentialcondition in the "cretinoid" affection occasionally observed in middle-aged women.Medico-Chir Trans 1878; 61: 57.

9.1.3. Reverdin JL: In discussion. Société médicale de Genève. Rev Med Suisse Ro-mande 1882; 2: 539.

9.1.4. Kocher T: Ueber Kropfexstirpation und ihre Folgen. Arch Klin Chir 1883; 29:254.

9.1.5. Report of a Committee of the Clinical Society of London to Investigate the Sub-ject of Myxedema. London, Longmans. Green & Co. Ltd. 1888.

REFERENCES-Section 9.2

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9.2.1. Spencer CA, LoPresti JS, Guttler RB, et al.: Application of a new chemilumines-cent thyrotropin assay to subnormal measurements. J Clin Endocrinol Metab 1990;70: 453-460.

9.2.2. Wiersinga WM. Adult hypothyroidism and myxedema coma. In: DeGroot LJ,Jameson JL (eds): Endocrinology (5th ed.). Philadelphia, WB Saunders Company,2004, ch. 107

9.2.3. Evered DC, Ormston BJ, Smith PA, et al.: Grades of hypothyroidism. Brit MedJ 1973; 1: 657-662.

9.2.4. Ishii H, Inada M, Tanaka K, et al.: Induction of outer and inner ring monodeio-dinases in human thyroid gland by thyrotropin. J Clin Endocrinol Metab 1983; 57:500-505.

9.2.5. Laurberg P: Mechanisms governing the relative proportions of thyroxine and3,5,3’-triiodothyronine in thyroid secretion.Metabolism 1984; 33: 379-392.

9.2.6. Lum SM, Nicoloff JT, Spencer CA, Kaptein EM: Peripheral tissue mechanismfor maintenance of serum triiodothyronine values in a thyroxine-deficient state inman. J Clin Invest 1984; 73: 570-575.

9.2.7. Martino E, Bartalena L, Pinchera A. Central hypothyroidism. In: Braverman LE,Utiger RD (eds): The Thyroid: A Fundamental and Clinical Text (8th ed.). Philadel-phia, JB Lippincott Williams & Wilkins, 2000, pp 762-773.

9.2.8. Tunbridge WMG, Evered DC, Hall R, et al.: The spectrum of thyroid disease inthe community: the Whickham Survey. Clin Endocrinol 1977; 7: 481-493.

9.2.9. Vanderpump MPJ, Tunbridge WMG, French JM, et al.: The incidence of thyroiddisorders in the community: a twenty-year follow-up of the Whickham Survey. ClinEndocrinol 1995; 43: 55-68.

9.2.10. Dos Remedios LV, Weber PM, Feldman R, et al.: Detecting unsuspected thyroiddysfunction by the free thyroxine index. Arch Intern Med 1980; 140: 1045-1049.

9.2.11. Sawin CT, Castelli WP, Hershman JM, et al.: The aging thyroid: Thyroid defi-ciency in the Framingham study. Arch Intern Med 1985; 145: 1386-1388.

9.2.12. Okamura K. Ueda K, Sone H, et al.: A sensitive TSH assay for screening ofthyroid functional disorder in elderly Japanese. J Am Geriatr Soc 1989; 37: 317-322.

9.2.13. Sundbeck G, Lundberg PA, Lindstedt G, et al.: Incidence and prevalence ofthyroid disease in elderly women: Results from the longitudinal population study ofelderly people in Gothenburg, Sweden. Age and Ageing 1991; 20: 291-298.

9.2.14. Wang C, Crapo LM: The epidemiology of thyroid disease and implication forscreening. Endocrinol Metab Clin North Am 1997; 26: 189-218.

9.2.15. Geul KW, van Sluisveld ILL, Grobbee DE, et al.: The importance of thyroidmicrosomal antibodies in the development of elevated serum TSH in middle-agedwomen: Associations with serum lipids. Clin Endocrinol 1993; 39: 275-280.

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9.3.1.2. Miura Y, Perkel VS, Papenberg KA, et al.: Concanavalin-A, lentil, and ricinlectin affinity binding characteristic of human thyrotropin: differences in the sialyla-tion of thyrotropin in sera of euthyroid, primary, and central hypothyroid patients. JClin Endocrinol Metab 1989; 69: 985-995.

9.3.1.3. Horimoto M, Nishikawa M, Ishihara T, et al.: Bioactivity of thyrotropin(TSH) in patients with central hypothyroidism: comparison between in vivo3,5,3’-triiodothyronine response to TSH and in vitro bioactivity of TSH. J ClinEndocrinol Metab 1995; 80: 1124-1128.

53


9.3.1.4. Samuels MH, Lillehei K, Kleinschmidt-Demasters BK, et al.: Patterns of pul-satile glycoprotein secretion in central hypothyroidism and hypogonadism. J ClinEndocrinol Metab 1990; 70: 391-395.

9.3.1.5. Adriaanse R, Brabant G, Endert E, Wiersinga WM: Pulsatile TSH release inpatients with untreated pituitary disease. J Clin Endocrinol Metab 1993; 77: 205-209.

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9.3.1.7. Dacou-Voutetakis C, Feltquate DM, Drakopoulo M, et al.: Familialhypothyroidism caused by a nonsense mutation in the thyroid-stimulating hormoneß-subunit gene. Am J Hum Genet 1990; 46: 988-993.

9.3.1.8. Hayashizaki Y, Hiraoka Y, Tatsumi K: Deoxyribonucleic acid analyses of fivefamilies with familial inherited thyroid stimulating hormone deficiency. J Clin En-docrinol Metab 1990; 71: 792-796.

9.3.1.9. Zegher F de, Pernasetti F, Vanhole C et al.: The prenatal role of thyroid hor-mone evidenced by fetomaternal Pit-1 deficiency. J Clin Endocrinol metab 1995; 80:3127-3130.

9.3.1.10. Arafah BM. Reversible hypopituitarism in patients with largenon-functioning pituitary adenomas. J Clin Endocrinol Metab 1986; 62: 1173-1179.11. Constine LS, Woolf PD, Cann D, et al.: Hypothalamic-pituitary dysfunction afterradiation for brain tumors. N Engl J Med 1993; 328: 87-94.

9.3.1.12. Snijder PJ, Fowble BF, Schatz NJ, et al.: Hypopituitarism following radiationtherapy of pituitary adenomas. Am J Med 1986; 81: 457-462.

9.3.1.13. Edwards BM, Clark JDA: Post-traumatic hypopituitarism: six cases and areview of the literature. Medicine 1986; 65: 281-290.

9.3.1.14. Cosman F, Post KD, Holub D, Wardlaw SL, et al.: Lymphocytic hypophysitis.Report of 3 new cases and review of the literature. Medicine 1989; 68: 240-256.

9.3.1.15. Kaptein EM, Spencer CA, Kamile MB, Nicoloff JT: Prolonged dopamine ad-ministration and thyroid hormone economy in normal and critically ill subjects. JClin Endocrinol Metab 1980; 51: 387-393.

9.3.1.16. Vagenakis AG, Braverman LE, Azizi F, et al.: Recovery of pituitary thy-rotropic function after withdrawal of prolonged thyroid suppression therapy. N EnglJ Med 1975; 293: 681-684.

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9.3.1.18. Oliveira JHA, Persani L, Beck-Peccoz P, et al. Investigating the paradoxof hypothyroidism and increased serum thyrotropin (TSH) levels in Sheehan’ssyndrome: characterization of TSH carbohydrate content and bioactivity. J ClinEndocrinol Metab 2001; 86: 1694-1699.

9.3.1.19. Bonomi M, Proverbio MC, Weber G, et al. Hyperplastic pituitary gland, highserum glycoprotein <61474>-subunit, and variable circulating thyrotropin (TSH) lev-els as hallmark of central hypothyroidism due to mutations of the TSH<61476> gene.J Clin Endocrinol Metab 2001; 86: 1600-1604.

9.3.1.20. Vuissoz JM, Deladoëy J, Buyukgebiz A et al. New autosomal recessive muta-tion of the TSH<61476> subunit gene causing central isolated hypothyroidism. J ClinEndocrinol Metab 2001; 86: 4468-4471.

9.3.1.21. Lando A, Holm K, Nysom K, et al. Thyroid function in survivors of child-hood acute lymphoblastic leukemia: the significance of prophylactic cranial irradia-tion. Clin Endocrinol 2001; 55: 21-25.

9.3.1.22. Rose SR. Cranial irradiation and central hypothyroidism. Trends EndocrinolMetab 2001; 12:97-104.

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9.3.1.23. Persani L, Ferretti E, Borgato S, et al. Circulating thyrotropin bioactivity insporadic central hypothyroidism. J Clin Endocrinol Metab 2000; 85:3631.

9.3.1.24. Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, et al. A Population-based study of thyroid function after radiotherapy and chemotherapy for a child-hood brain tumor. J Clin Endocrinol Metab 2003; 88:136-140.

9.3.1.25. Benvenga S, Campenmi A, Ruggeri RM, Trimarchi F. Hypopituitarism sec-ondary to head trauma. J Clin Endocrinol Metab 2000; 85:1353-136.

9.3.1.26. Bellastella A, Bizzarro A, Coronella C, et al. Lymphocytic hypophysitis: arare or underestimated disease? Eur J Endocrinol 2003; 149:363-376.

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9.3.2.1. Hayashi Y, Tamai H, Fukata S, et al.: A long-term clinical, immunological, andhistological follow-up study of patients with goitrous chronic lymphocytic thyroidi-tis. J Clin Endocrinol Metab 1985; 61: 1172-1178.

9.3.2.2.. Michaelson ED, Young RL: Hypothyroidism with Graves’ disease. JAMA1970; 23: 1351.

9.3.2.3. Arikawa K, Ichikawa Y, Yoshida T, et al.: Blocking type antithyrotropin recep-tor antibody in patients with nongoitrous hypothyroidism: its incidence and charac-teristics of action. J Clin Endocrinol Metab 1985; 60: 953-959

9.3.2.4. Kraiem Z, Lahat N, Glaser B, et al.: Thyrotropin receptor blocking antibodies:incidence, characterization and in vivo synthesis. Clin Endocrinol 1987; 27: 409-421

9.3.2.5. Rieu M, Portos C, Lissak B, et al.: Relationship of antibodies to thyrotropinreceptors and to thyroid ultrasonographic volume in euthyroid and hypothyroid pa-tients with autoimmune thyroiditis. J Clin Endocrinol Metab 1996; 80: 641-645.

9.3.2.6. Laurberg P, Pedersen KM, Hreidarsson A, et al.: Iodine intake and the patternof thyroid disorders: a comparative epidemiological study of thyroid abnormalitiesin the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab 1998; 83:765-769.

9.3.2.7. Sundrick RS, Bagchi N, Brown TR: The role of iodine in thyroid autoimmu-nity: from chickens to humans: a review. Autoimmunity 1992; 13: 61-68.

9.3.2.8. Kasagi K, Iwata M, Misaki T, Konishi J. Effect of iodine restriction on thyroidfunction in patients with primary hypothyroidism. Thyroid 2003; 13: 561-567.

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9.3.3.1. Nikolai TF: Recovery of thyroid function in primary hypothyroidism. Am JMed Sci 1989; 297: 18-21.

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9.3.3.3. Comtois R, Faucher L, Laflèche L: Outcome of hypothyroidism caused byHashimoto’s thyroiditis. Arch Int Med 1995; 155: 1404-1408.

9.3.3.4. Takasu N, Komiya I, Asawa T, et al.: Test for recovery from hypothyroidismduring thyroxine therapy in Hashimoto’s thyroiditis. Lancet 1990; 336: 1084-1086.

9.3.3.5. Takasu N, Yamada T, Takasu M, et al.: Disappearance of thyrotropin-blockingantibodies and spontaneous recovery from hypothyroidism in autoimmune thyroidi-tis. N Eng J Med 1992; 326: 513-518.

9.3.3.6. Kraiem Z, Baron E, Kahana L, et al.: Changes in stimulating and blockingTSH receptor antibodies in a patient undergoing three cycles of transition from hypoto hyperthyroi-dism and back to hypothyroidism. Clin Endocrinol 1992; 36: 211-216.

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9.3.3.7. Gerstein HC: How common is postpartum thyroiditis? A methodologicoverview of the literature. Arch Int Med 1990; 150: 1397-1400.

9.3.3.8. Kuypens JL, Pop VJ, Vader HL, et al.: Prediction of postpartum thyroid dys-function: can it be improved? Eur J Endocrinol 1998; 139: 36-43.

9.3.3.9. Alvarez-Marfany M, Roman SH, Drexler AJ, et al.: Long-term prospectivestudy of postpartum thyroid function in women with insulin dependent diabetesmellitus. J Clin Endocrinol Metab 1994; 79: 10-16.

9.3.3.10. Othman S, Phillips DI, Parkes AB, et al.: A long-term follow-up of postpar-tum thyroiditis. Clin Endocrinol 1990; 32: 559-564.

9.3.3.11. Kuypens JL, de Haan-Meulman M, Vader HL, et al.: Cell-mediated immunityand postpartum thyroid dysfunction: a possibility for the prediction of disease? J ClinEndocrinol Metab 1998; 83: 1959-1966.

9.3.3.12. Harris B, Othman S, Davies JA, et al.: Association between postpartum thy-roid dysfunction and thyroid antibodies and depression. Brit Med J 1992; 305: 152-156.

9.3.3.13. Pop VJ, de Vries E, van Baar A, et al.: Maternal thyroid peroxidase antibodiesduring pregnancy: a marker of impaired child development? J Clin Endocrinol Metab1995; 80: 3561-3566.

9.3.3.14. Pop VJ, Kuypens JL, Van Baar AL, et al.: Low maternal free thyroxine con-centrations during early pregnancy are associated with impaired psychomotor de-velopment in infancy. Clin Endocrinol 1999; 50: 149-156.

9.3.3.15. Vialettes B, Guillerand MA, Viens P, et al.: Incidence rate and risk factors forthyroid dysfunction during recombinant interleukin-2 therapy in advanced malig-nancies. Acta Endocrinol 1993; 129: 31-38.

9.3.3.16. Preziati D, La Rosa L, Covini G, et al.: Autoimmunity and thyroid function inpatients with chronic active hepatitis treated with recombinant interferon alpha-2a.Europ J Endocrinol 1995; 132: 587-593.

9.3.3.17. Marazuela M, Garcia-Buey L, Gonzalez-Fernandez B, et al.: Thyroid autoim-mune disorders in patients with chronic hepatitis C before and during interferon-atherapy. Clin Endocrinol 1996; 44: 635-642.

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9.3.4.1. Nofal MN, Beierwaltes WH, Patno ME: Treatment of hyperthyroidism withsodium iodide I-131, a 16-year experience. JAMA 1966; 197: 605-610.

9.3.4.2. Hagen GA, Ouellette RP, Chapman EM: Comparison of high and low dosageof 131I in the treatment of thyrotoxicosis. N Engl J Med 1967; 277: 559.

9.3.4.3. Roudebush CP, Hoye KE, DeGroot LJ: Compensated low-dose 131I therapyof Graves’ disease. Ann Intern Med 1977; 87: 441.

9.3.4.4. Nygaard B, Hegedüs L, Gervil M, et al.: Influence of compensated 131I ther-apy on thyroid volume and incidence of hypothyroidism in Graves’ disease. J IntMed 1995; 238: 491-497.

9.3.4.5. Stoffer SS, Hamburger JI: Inadvertent 131I therapy for hyperthyroidism in thefirst trimester of pregnancy. J Nucl Med 1976; 17: 146.

9.3.4.6. Huysmans DA, Corstens FH, Kloppenborg PW: Long-term follow-up in toxicsolitary autonomous thyroid nodules treated with radioactive iodine. J Nucl Med1991; 32: 27-30.

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9.3.4.8. Smith RE, Adler RA, Clark P, et al.: Thyroid function after mantle irradiationin Hodgkin’s disease. JAMA 1981; 245: 46-49.

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9.3.5.1. Chau AM, Lynch MJG, Bailey JD et al.: Hypothyroidism in cystinosis: a clin-ical, endocrinologic and histologic study involving sixteen patients with cytinosis.Am J Med 1970; 48: 678.

9.3.5.2. Barsano CP: Other forms of hypothyroidism. In: Braverman LE, Utiger RD(eds): The Thyroid: A Fundamental and Clinical Text (7th ed.). Philadelphia, JB Lip-pincott, 1996, pp 768-778.


9.3.7.1. Wiersinga WM, Touber JL, Trip MD, van Royen EA: Uninhibited thyroidaluptake of radioiodine despite iodine excess in amiodarone-induced hypothyroidism.J Clin Endocrinol Metab 1986; 63: 485-491.

9.3.7.2. Braverman LE: Iodine and the thyroid: 33 years of study. Thyroid 1994; 4:351-356.b 9.3.7.3. Okamura K, Sato K, Ikenoue H, et al.: Reevaluation of thyroidalradioactive iodine uptake test, with special reference to reversible primary hypothy-roidism with elevated thyroid radioiodine uptake. J Clin Endocrinol Metab 1988; 67:720-726.

9.3.7.3. Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG.Iodine-induced hypothyroidism. Thyroid 2001; 11: 501-510.

9.3.7.4. Trip MD, Wiersinga WM, Plomp TA: Incidence, predictability, and pathogen-esis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med 1991; 91:507-511.

9.3.7.5. Martino E, Safran M, Aghini-Lombardi F, et al.: Environmental iodine intakeand thyroid dysfunction during chronic amiodarone therapy. Ann Int Med 1984; 101:28-34.


9.3.8.1. Braverman LE, Woeber KA, Ingbar SH: Induction of myxedema by iodide inpatients euthyroid after radioiodine or surgical treatment of diffuse toxic goiter. NEngl J Med 1969; 281: 816.

9.3.8.2. Braverman LE, Ingbar SH, Vagenakis AG, et al.: Enhanced susceptibility toiodide myxedema in patients with Hashimoto’s thyroiditis. J Clin Endocrinol 1971;32: 515

9.3.8.3. Berens SC, Bernstein RS, Robbins J, Wolff J: Antithyroid effects of lithium. JClin Invest 1970; 49: 1357.

9.3.8.4. Perrild H, Hegedüs L, Baastrup PC, et al.: Thyroid function and ultrasoni-cally determined thyroid size in patients receiving long-term lithium treatment. AmJ Psychiatry 1990; 147: 1508-1521.

9.3.8.5. Gaitan E, Cooksey RC, Legan J, et al.: Antithyroid and goitrogenic effects ofcoal-water extracts from iodine-sufficient goiter areas. Thyroid 1993; 3 49-53.

9.3.8.6. Langer P, Tajtakova M, Fodor G, et al.: Increased thyroid volume and preva-lence of thyroid disorders in an area heavily polluted by polychlorinated biphenyls.Eur J Endocrinol 1998; 139: 402-409.



9.3.9.1. Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type3 iodothyronine deiodinase in infantile hemangiomas. New Engl J Med 2000; 343:185-189.

9.3.9.2. Huang SA, Fish SA, Dorfman DM et al. A 21-year-old woman with consump-tive hypothyroidism due to a vascular tumor expressing type 3 iodothyronine deio-dinase. J Clin Endocrinol Metab 2002; 87: 4457-4461.

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9.4.5. Wilkens L: Epiphysial dysgenesis associated with hypothyroidism. Am J DisChild 1941; 61: 13.

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9.4.9. Salomon MI, DiScala V, Grisham E et al: Renal lesions in hypothyroidism: astudy based on kidney biopsies. Metabolism 1967; 16: 846.

9.4.10. Ezrin C, Swanson HE, Humphrey JG et al: The cells of the human adenohy-pophysis in thyroid disorders. J Clin Endocrinol Metab 1959; 19: 958.

9.4.11. Yamada T, Tsukui T, Ikejiri K et al: Volume of sella turcica in normal sub-jects and in patients with primary hypothyroidism and hyperthyroidism. J Clin En-docrinol Metab 1976; 42: 817.

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9.5.1.1. Diekman MJM, Romijn JA, Endert E, Sauerwein H, Wiersinga WM. Thyroidhormones modulate serum leptin levels: observations in thyrotoxic and hypothyroidwomen. Thyroid 1998; 8: 1081-1086.

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9.5.1.8. Shah JH, Motto GS, Papagiannes E, William GA: Insulin metabolism in hy-pothyroidism. Diabetes 1975; 24: 922.

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9.5.1.10. Hecht A, Gershberg H: Diabetes mellitus and primary hypothyroidism.Metabolism 1968; 17: 108.

9.5.1.11. Abrams JJ, Grundy SM: Cholesterol metabolism in hypothyroidism and hy-perthyroidism in man. J Lipid Res 1981; 22: 323.

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9.5.1.13. Kurland GS, Lucas JL, Freedberg AS: The metabolism of intravenously in-fused 14C-labeled cholesterol in euthyroidism and myxedema. J Lab Clin Med 1961;57: 574.

9.5.1.14. Walton KW, Scott PJ, Dykes PW, Davies JWL: The significance of alterationsin serum lipids in thyroid dysfunction. II. Alterations of the metabolism and turnoverof 131I low-density lipoproteins in hypothyroidism and thyrotoxicosis. Clin Sci 1965;29: 217.

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9.5.1.16. Scarabottolo L, Trezzi E, Roma P, Gatapano AL: Experimentalhypothyroidism modulates the expression of the low density lipoprotein receptorby the liver. Atherosclerosis 1986; 59: 329.

9.5.1.17. Thompson GR, Soutar AK, Spengel FA, et al: Defects of receptor mediatedlow density lipoprotein catabolism in homozygous familial hypercholesterolemiaand hypothyroidism in vivo. Proc Natl Acad Sci USA 1981; 78: 2591.

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9.5.1.19. O’Brien T, Katz K, Hodge D, et al.: The effect of treatment of hypothyroidismand hyperthyroidism on plasma lipids and apolipoproteins AI, AII and E. Clin En-docrinol 1997; 46: 17-20.

9.5.1.20. Dullaart RPF, Hoogenberg K, Groener JEM, et al.: The activity of cholesterolester transfer protein is decreased in hypothyroidism: a possible contribution to al-terations in high-density lipoproteins. Europ J Clin Invest 1990; 20: 581-587.

9.5.1.21. Tan KCB, Shiu SWM, Kung AWC: Plasma cholesteryl ester transfer proteinactivity in hyper- and hypothyroidism. J Clin Endocrinol Metab 1998; 83: 140-143.9.5.1.22. Martinez-Triguero ML, Hernandez-Myares A, Nguyen TT, et al.: Effect ofthyroid hormone replacement on lipoprotein (a), lipids, and apolipoproteins in sub-jects with hypothyroidism. Mayo Clin Proc 1998; 73: 837-841.

9.5.1.22. Diekman MJM, Anghelescu N, Endert E, Bakker O, Wiersinga WM. Changesin plasma low-density lipoprotein (LDL)- and high-density lipoprotein cholesterolin hypo- and hyperthyroid patients are related to changes in free thyroxine, not topolymorphisms in LDL receptor or cholesterol ester transfer protein genes. J ClinEndocrinol Metab 2000; 85: 1857-1862.

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9.5.2.1. Smith TJ, Murata Y, Horwitz AL et al: Regulation of glycosaminoglycan accu-mulation by thyroid hormone in vitro. J Clin Invest 1982; 70 1066.

9.5.2.2. Aikawa JK: The nature of myxedema: Alterations in the serum electrolyte con-centrations and radiosodium space and in the exchangeable sodium and potassiumcontents. Ann Intern Med 1956; 44: 30.

9.5.2.3. Crispell KR, Williams GA, Parson W, Hollifeld G: Metabolic studies inmyxedema following administration of l-triiodothyronine: (1) Duration of negativenitrogen balance: (2) effect of testosterone proprionate: (3) comparison with nitrogenbalance in a healthy volunteer. J Clin Endocrinol Metab 1957; 17: 221.

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9.5.3.1. Smith CD, Ain KB: Brain metabolism in hypothyroidism studied with 31Pmagnetic-resonance spectroscopy. Lancet 1995; 345: 619-620.

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9.5.3.5. Cremer GM, Goldstein NP, Paris J: Myxedema and ataxia. Neurology 1969;19: 37.

9.5.3.6. Crevasse LE, Logue RB: Peripheral neuropathy in myxedema. Ann InternMed 1959;50: 1433.

9.5.3.7. Nickel SN, Frame B: Nervous and muscular systems in myxedema. J ChronicDis 1961; 14: 570.

9.5.3.8. Murray IPC, Simpson JA: Acroparaesthesia in myxoedema. Lancet 1958; 1:1360.

9.5.3.9. Bland JH, Frymoyer JW: Rheumatoid syndrome of myxedema. N Engl J Med1970; 282: 1171.

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9.5.3.19. Scheinberg P, Stead EA, Braman ES, Warren JV: Correlative observations oncerebral metabolism. J Clin Invest 1950; 29: 1139.

9.5.3.20. Sensenbach W, Madison L, Eisenberg S, Ochs L: The cerebral circulation andmetabolism in hyperthyroidism and myxedema. J Clin Invest 1954; 33: 1434

9.5.3.21. O’Brien MD, Harris PWR: Cerebral-cortex perfusion rates in myxedema.Lancet 1965; 1: 1170.

9.5.3.22. Duyff RF, Bosch J vd, Laman DM, et al. Neuromuscular findings in thyroiddysfunction: a prospective clinical and electrodiagnostic study. J Neurol NeurosurgPsychiatry 2000; 68: 750-755.

9.5.3.23. Gunarsson T, Sjöberg S, Eriksson M, Nordin C. Depressive symptoms inhypothyroid disorder with some observations on biochemical correlates. Neuropsy-chobiology 2001; 43: 70-74.

9.5.3.24. Kinuya S, Michigiski T, Tonami N, et al. Reversible cerebral hypoperfusionobserved with Tc-99m HMPAO SPECT in reversible dementia caused by hypothy-roidism. Clin Nucl Med 1999; 24: 666-668.

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9.5.5.1. Wilson WR, Bedell GN: The pulmonary abnormalities in myxedema. J ClinInvest 1960; 39: 42.

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9.5.5.3. Nordqvist P, Dhunér KG, Stenberg K, Örndahl G: Myxedema coma and CO2retention. Acta Med Scand 1960; 166; 189.

9.5.5.4. Weg JG, Calverly JR, Johnson C: Hypothyroidism and alveolar hypoventila-tion. Arch Intern Med 1965; 115: 302.

9.5.5.5. Orr WC, Males JL, Imes NK: Myxedema and obstructive sleep apnea. Am JMed 1981; 70: 1061

9.5.5.6. Ladenson PW, Goldenheim PD, Ridgway EC: Prediction and reversal ofblunted ventilatory responsiveness in patients with hypothyroidism. Am J Med1988: 84: 877-883.

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9.5.6.1. Kaminsky P, Robin-Lherbier B, Brunotte F, et al.: Energetic metabolism inhypothyroid skeletal muscle, as studied by phosphorus magnetic resonance spec-troscopy. J Clin Endocrinol Metab 1992; 74: 124-129.

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9.5.6.7. Thomasen E: Myotonia, Thomsen’s Disease, Paramyotonia, Dystrophia My-otonica, Aarhus, Denmark, Universitetsforlaget, 1948.

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9.5.6.13. Frymoyer JW, Bland JH: Carpal-tunnel syndrome in patients with myxede-matous arthropathy. J Bone Joint Surg 1973; 55A: 78.

9.5.6.14. Bonakdarpour A, Kirkpatrick JA, Renzi A, Kendall N: Skeletal changes inneonatal thyrotoxicosis. Radiology 1972; 102: 149.

9.5.6.15. Krane S, Bronwell GL, Stanbury JB, Corrigan H: The effect of thyroid diseaseon calcium metabolism in man. J Clin Invest 1956; 35: 874.

9.5.6.16. Bouillon R, De Moor P: Parathyroid function in patients with hyper- or hy-pothyroidism. J Clin Endocrinol Metab 1974; 38: 999.

9.5.6.17. Lever EG: Primary hyperparathyroidism masked by hypothyroidism. Am JMed 1983; 74: 144.

9.5.6.18. Lave CE, Bird ED, Thomas WC: Hypercalcemia in myxedema. J Clin En-docrinol Metab 1962; 22: 261.

9.5.6.19. Bouillon R, Muls E, De Moor P: Influence of thyroid function on the serumconcentration of 1,25-dihydroxy vitamin D3. J Clin Endocrinol Metab 1980; 51: 793.

9.5.6.20. Mundy GR, Shapiro JL, Bandelin JG, et al.: Direct stimulation of bone resorp-tion by thyroid hormones. J Clin Invest 1976; 58: 529.

9.5.6.21. Eriksen EF: Normal and pathological remodeling of human trabecular bone:Three dimensional reconstruction of the remodeling sequence in normals and inmetabolic bone disease. Endocr Rev 1986; 7: 379.

9.5.6.22. Duyff RF, Bosch J vd, Laman DM, et al. Neuromuscular findings in thyroiddysfunction: a prospective clinical and electrodiagnostic study. J Neurol NeurosurgPsychiatry 2000; 68: 750-755.

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9.5.7.1. Lerman J, Means JH: The gastric secretion in exophthalmic goitre and myx-oedema. J Clin Invest 1932; 11: 167.

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9.5.7.7. Broitman SA, Bondy DC, Yachnin I et al.: Absorption and disabsorption ofD-xylose in thyrotoxicosis and myxedema. N Engl J Med 1964; 270: 333.

9.5.7.8. Depczynski B, Ward R, Eisman J: The association between myxedematousascites and extreme elevation of serum tumor markers. J Clin Endocrinol Metab 1996;81: 4175.

9.5.7.9. Fleisher G, McConahey W, Pankow M: Serum creatine kinase, lactic dehy-drogenase, and glutamic-oxalacetic transaminase in thyroid diseases and pregnancy.Mayo Clinic Proc 1965; 40: 300.

9.5.7.10. Amino N, Kuro R, Yabu Y, et al.: Elevated levels of circulating carcinoembry-onic antigens in hypothyroidism. J Clin Endocrinol Metab 1981; 52: 457.

9.5.7.11. Lorenzo y Losade H Jr, Staricco EC, Cervino JM, et al.: Hypotonia of thegallbladder, of myxedematous origin. J Clin Endocrinol Metab 1957; 17: 133.

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9.5.8.1. Nedreb BG, Ericsson U-B, Nygård O, et al.: Plasma total homocysteine levelsin hyperthyroid and hypothyroid patients. Metabolism 1998; 47: 89-93.

9.5.8.2. Yount E, Little JM: Renal clearance in patients with myxedema. J Clin En-docrinol Metab 1955; 15: 343.

9.5.8.3. Discala VA, Kinney MJ: Effects of myxedema on the renal diluting and con-centrating mechanism. Am J Med 1971; 50: 325

9.5.8.4. Ford RV, Owens JC, Curd GW Jr et al.: Kidney function in various thyroidstates. J Clin Endocrinol Metab 1961; 21: 548.

9.5.8.5. Moses AM, Gabrilove JL, Soffer LJ: Simplified water loading test in hypoad-renocorticism and hypothyroidism. J Clin Endocrinol Metab 1958; 18: 1413.

9.5.8.6. Crispell KR, Parson W, Sprinkle P: A cortisone-resistant abnormality in thediuretic response to ingested water in primary myxedema. J Clin Endocrinol Metab1954; 14: 640.

9.5.8.7. Bleifer KH, Belsky JL, Saxon L, Papper S: The diuretic response to adminis-tered water in patients with primary myxedema. J Clin Endocrinol Metab 1960; 20:409.

9.5.8.8. Davies CE, MacKinnon J, Platts MM: Renal circulation and cardiac output in"low-output" heart failure and in myxoedema. Br Med J 1952; 2: 595.

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9.5.8.15. Jones JE, Desper PC, Shane SR, Flink EB: Magnesium metabolism in hyper-thyroidism and hypothyroidism. J Clin Invest 1966; 45: 891.

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9.5.9.1. De La Balze FA, Arrillaga F, Mancini RE, et al.: Male hypogonadism in hy-pothyroidism: a study of six cases. J Clin Endocrinol Metab 1962; 22: 212.

9.5.9.2. Davis LE, Leveno KJ, Cunningham FG: Hypothyroidism complicating preg-nancy. Obstet Gynecol 1988; 72: 108.

9.5.9.3. Potter JD: Hypothyroidism and reproductive failure. Surg Gynecol Obstet1980; 150: 251.

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9.5.9.5. Montoro M, Collea JV, Frasier SD, Mestman JH: Successful outcome of preg-nancy in women with hypothyroidism. Ann Intern Med 1981; 94: 31.

9.5.9.6. Liu H, Momotani N, Noh JY et al.: Maternal hypothyroidism during earlypregnancy and intellectual development of progeny. Arch Intern Med 1994; 154: 785.

9.5.9.7. Man EB, Brown JF, Serunian SA: Maternal hypothyroxinemia: Psychoneuro-logical deficits of progeny. Ann Clin Lab Ser 1991; 21 227.

9.5.9.8. Krassas GE, Pontikides N, Kaltsas Th, Papadopoulou PL, Paunkovic J,Paunkovic N, Duntas LE. Disturbances of menstruation in hypothyroidism. ClinEndocrinol 1999; 50: 655-659.

9.5.9.9. Ross GT, Scholz DA, Lamberg EH, Geraci JE: Severe uterine bleeding anddegenerative skeletal-muscle changes in unrecognized myxedema. J Clin EndocrinolMetab 1958; 18: 492.

9.5.9.10. Goldsmith RE, Sturgis SH, Lerman J, Stanbury JB: The menstrual pattern inthyroid disease. J Clin Endocrinol Metab 1952; 12: 846.

9.5.9.11. Samuels MH, Veldhuis JD, Henry P, Ridgway EC: Pathophysiology of pul-satile and copulsatile release of thyroid-stimulating hormone, luteinizing hormone,follicle-stimulating hormone, and apha-subunit. J Clin Endocrinol Metab 1990; 71:425-432.

9.5.9.12. Ross F, Nusynowitz ML: A syndrome of primary hypothyroidism, amenor-rhea and galactorrhea. J Clin Endocrinol 1968; 28: 591.

9.5.9.13. Costin G, Kershnar AK, Kogut MD, Turkington RW: Prolactin activity injuvenile hypothyroidism and precocious puberty. Pediatrics 1972; 50: 881.

9.5.9.14. Hopwood NJ, Lockhart LH, Bryan GT: Acquired hypothyroidism with mus-cular hypertrophy and precocious testicular enlargement. J Pediatr 1974; 85: 233

9.5.9.15. Bruder JM, Samuels MH, Bremner WJ, et al.: Hypothyroidism-inducedmacroorchidism: use of a gonadotropin-releasing hormone agonist to understand itsmechanism and augment adult stature. J Clin Endocrinol Metab 1995; 80: 11-16.

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9.5.9.17. Anderson DC: Sex-hormone-binding globulin. Clin Endocrinol 1974; 3: 69.

9.5.9.18. Gordon GG, Southren AL: Thyroid-hormone effects on steroid-hormonemetabolism. Bull NY Acad Med 1977; 53: 241.

9.5.9.19. Copinschi G, Leclercq R, Bruno OD, Cornil A: Effects of altered thyroid func-tion upon cortisol secretion in man. Horm Metab Res 1971; 3: 437.

9.5.9.20. Gordon GG, Southern AL, Tochimoto S, et al.: Effect of hyperthyroidism andhypothyroidism on the metabolism of testosterone and androstenedione in man. JClin Endocrinol Metab 1969; 29: 164.

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9.5.10.1. Yamada T, Tsukui T, Ikejiri K, et al.: Volume of sella turcica in normal sub-jects and in patients with primary hypothyroidism and hyperthyroidism. J Clin En-docrinol Metab 1976; 42: 817.

9.5.10.2. Yamamoto K, Saito K, Takai T, et al.: Visual field defects and pituitary en-largement in primary hypothyroidism. J Clin Endocrinol Metab 1983; 57: 283.

9.5.10.3. Vagenakis AG, Dole K, Braverman LE: Pituitary enlargement, pituitary fail-ure, and primary hypothyroidism. Ann Intern Med 1976; 85: 195.

9.5.10.4. Sarlis NJ, Brucker-Davis F, Doppman JL, Skarulis MC: MRI-demonstrableregression of a pituitary mass in a case of primary hypothyroidism after a week ofacute thyroid hormone therapy. J Clin Endocrinol Metab 1997; 82: 808-811.

9.5.10.5. Honbo KS, Van Herle AJ, Kellett KA: Serum prolactin levels in untreatedprimary hypothyroidism. Am J Med 1978; 64: 782.

9.5.10.6. Onishi T, Miyai K, Aono T, et al.: Primary hypothyroidism and galactorrhea.Am J Med 1977; 63: 373.

9.5.10.7. Brauman H, Corvilain J: Growth hormone response to hypoglycemia inmyxedema. J Clin Endocrinol Metab 1968; 28: 301.

9.5.10.8. Valcavi R, Valente F, Dieguez C, et al.: Evidence against depletion of thegrowth hormone (GH)-releasable pool in human primary hypothyroidism: studieswith GH-releasing hormone, pyridostigmine, and arginine. J Clin Endocrinol Metab1993; 77: 616-620.

9.5.10.9. Miell JP, Taylor AM, Zini M, et al.: Effects of hypothyroidism and hyperthy-roidism on insulin-like growth factors (IGFs) and growth hormone- and IGF-bindingproteins. J Clin Endocrinol Metab 1993; 76: 950.

9.5.10.10. Miell JP, Zini M, Quin JD, et al.: Reversible effects of cessation and recom-mencement of thyroxine treatment on insulin-like growth factors (IGFs) and IGF-binding proteins in patients with toal thyroidectomy. J Clin Endocrinol Metab 1994;79: 1507-1512.

9.5.10.11. Gordon GG, Southren AL: Thyroid-hormone effects on steroid-hormonemetabolism. Bull NY Acad Med 1977; 53: 241.

9.5.10.12. Brown H, Englert E, Wallach S: Metabolism of free and conjugated 17-hydroxycorticosteroids in subjects with thyroid disease. J Clin Endocrinol Metab1958; 18: 167.

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9.5.10.13. Copinschi G, Leclercq R, Bruno OD, Cornil A: Effects of altered thyroidfunction upon cortisol secretion in man. Horm Metab Res 1971; 3: 437.

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Chapter9 Adult Hypothyroidism